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 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
September 2022 
ICH 
 
 
Revision 2
  Contains Nonbinding Recommendations 
 
FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry.  
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1) ....................................................................................................... 1 
II.  SCOPE (2).......................................................................................................................... 2 
III.  SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES (3) ......... 2 
A.  Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and 
Inhalation Routes of Administration (3.1) ................................................................................... 3 
B.  Other Routes of Administration (3.2) .......................................................................................... 4 
C.  Justification for Elemental Impurity Levels Higher Than an Established PDE (3.3) ............. 4 
D.  Parenteral Products (3.4) .............................................................................................................. 5 
IV.  ELEMENT CLASSIFICATION (4) ............................................................................... 6 
V.  RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES (5) ........ 7 
A.  General Principles (5.1) ................................................................................................................. 7 
B.  Potential Sources of Elemental Impurities (5.2) .......................................................................... 8 
C.  Identification of Potential Elemental Impurities (5.3) ................................................................ 9 
D.  Recommendations for Elements To Be Considered in the Risk Assessment (5.4) .................. 10 
E.  Evaluation (5.5) ............................................................................................................................ 11 
F.  Summary of Risk Assessment Process (5.6) ............................................................................... 12 
G.  Special Considerations for Biotechnologically-Derived Products (5.7) ................................... 13 
VI.  Control of Elemental Impurities (6) ........................................................................................... 13 
VII.  Converting Between PDEs and Concentration Limits (7)........................................................ 14 
VIII.  Speciation and Other Considerations (8) ................................................................................... 16 
IX.  Analytical Procedures (9) ............................................................................................................ 17 
X.  Lifecycle Management (10) ......................................................................................................... 17 
REFERENCES .......................................................................................................................................... 22 
Appendix 1: Method for Establishing Exposure Limits ........................................................................ 23 
Appendix 2: Established PDEs for Elemental Impurities ..................................................................... 26 
Appendix 3: Individual Safety Assessments ........................................................................................... 28 
Appendix 4: Illustrative Examples .......................................................................................................... 82 
Appendix 5:  Limits for Elemental Impurities by the Cutaneous and Transcutaneous Route ... 90 
TABLE OF CONTENTS ........................................................................................................ 90 
I.  BACKGROUND (1)........................................................................................................ 91 
II.  SCOPE (2)  ....................................................................................................................... 92 
i  Contains Nonbinding Recommendations 
 
III.  PRINCIPLES OF SAFETY ASSESSMENT FOR CUTANEOUS PRODUCTS (3)      
  ........................................................................................................................................... 92 
A.  Transcutaneous Absorption of Elemental Impurities (EI) (3.1) .............................................. 92 
B.  PDE for Drug Products Directly Applied to the Dermis (3.2) ................................................. 93 
IV.  ESTABLISHING THE CUTANEOUS PERMITTED DAILY EXPOSURE (PDE) 
(4)  ........................................................................................................................................... 93 
A.  Establishing the Cutaneous Modifying Factor (CMF) (4.1) ..................................................... 93 
B.  Cutaneous PDE (4.2) .................................................................................................................... 94 
4.2.1  Derivation of PDE for EI, other than Arsenic (As) and Thallium (Tl) ............................... 94 
4.2.2  Derivation of PDE for Arsenic .............................................................................................. 94 
4.2.3  Derivation of PDE for Thallium ........................................................................................... 95 
V.  CUTANEOUS CONCENTRATION LIMITS FOR NI AND CO (5) ........................ 95 
VI.   PRODUCT RISK ASSESSMENT (6) ........................................................................... 95 
VII.  CUTANEOUS PDE VALUES (7).................................................................................. 96 
VIII. REFERENCES (8) ......................................................................................................... 98 
ii  Contains Nonbinding Recommendations 
 
1  Q3D(R2) ELEMENTAL IMPURITIES 
2  Guidance for Industry1 
3   
4   
5  This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
6  this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
7  can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
8  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
9  title page.   
10   
11   
12   
13  I.  INTRODUCTION (1)2 
14   
15  Elemental impurities in drug products may arise from several sources; they may be residual 
16  catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through 
17  interactions with processing equipment or container/closure systems or by being present in 
18  components of the drug product). Because elemental impurities do not provide any therapeutic 
19  benefit to the patient, their levels in the drug product should be controlled within acceptable limits. 
20  There are three parts of this guidance:  
21   
22    The evaluation of the toxicity data for potential elemental impurities  
23    The establishment of a Permitted Daily Exposure (PDE) for each element of toxicological 
24  concern 
25    The application of a risk-based approach to control elemental impurities in drug products  
26   
27  An applicant is not expected to tighten the limits based on process capability, provided that the 
28  elemental impurities in drug products do not exceed the PDEs. The PDEs established in this 
29  guidance are considered to be protective of public health for all patient populations. In some 
30  cases, lower levels of elemental impurities may be warranted when levels below toxicity 
31  thresholds have been shown to have an impact on other quality attributes of the drug product 
32  (e.g., element catalyzed degradation of drug substances). In addition, for elements with high 
33  PDEs, other limits may have to be considered from a pharmaceutical quality perspective and 
34  other guidances should be consulted such as the ICH guidance for industry Q3A(R2) Impurities 
35  in New Drug Substances (June 2008) (ICH Q3A(R2)).3 
36   
 
1 This guidance was developed within the Quality Expert Working of the International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to 
consultation by the regulatory parties, in accordance with the ICH process.  This document has been endorsed by the 
ICH Assembly at Step 4 of the ICH process, April 26, 2022.  At Step 4 of the process, the final draft is 
recommended for adoption to the regulatory bodies of the ICH regions.  
2 The numbers in parentheses reflect the organizational breakdown of the document endorsed by the ICH Assembly 
at Step 4 of the ICH process, April 26, 2022.  
3 See the ICH guidance for industry Q3A(R2) Impurities in New Drug Substances (June 2008). We update 
guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information  
  1  Contains Nonbinding Recommendations 
 
37  This guidance presents a process to assess and control elemental impurities in the drug product 
38  using the principles of risk management as described in the ICH guidance for industry Q9 
39  Quality Risk Management (June 2006) (ICH Q9).4 This process provides a platform for 
40  developing a risk-based control strategy to limit elemental impurities in the drug product. 
41   
42  The contents of this document do not have the force and effect of law and are not meant to bind 
43  the public in any way, unless specifically incorporated into a contract. This document is intended 
44  only to provide clarity to the public regarding existing requirements under the law. FDA 
45  guidance documents, including this guidance, should be viewed only as recommendations, unless 
46  specific regulatory or statutory requirements are cited.  The use of the word should in Agency 
47  guidance means that something is suggested or recommended, but not required. 
48   
49  II.  SCOPE (2) 
50   
51  The guidance applies to new finished drug products (as defined in the ICH guidances for 
52  industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances 
53  and New Drug Products: Chemical Substances (December 2000 (ICH Q6A) and Q6B 
54  Substances: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products 
55  (August 1999) (ICH Q6B)5 and new drug products containing existing drug substances. The drug 
56  products containing purified proteins and polypeptides (including proteins and polypeptides 
57  produced from recombinant or non-recombinant origins), their derivatives, and products of 
58  which they are components (e.g., conjugates) are within the scope of this guidance, as are drug 
59  products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides. 
60   
61  This guidance does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, 
62  DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood 
63  derivatives including plasma and plasma derivatives, dialysate solutions not intended for 
64  systemic circulation, and elements that are intentionally included in the drug product for 
65  therapeutic benefit. This guidance does not apply to products based on genes (gene therapy), cells 
66  (cell therapy) and tissue (tissue engineering). In some regions, these products are known as 
67  advanced therapy medicinal products. 
68   
69  This guidance does not apply to drug products used during clinical research stages of 
70  development. As the commercial process is developed, the principles contained in this guidance 
71  can be useful in evaluating elemental impurities that may be present in a new drug product. 
72   
73  Application of Q3D to existing products is not expected prior to 36 months after publication of 
74  the guidance by ICH. 
75   
76  III.  SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES (3)   
 
4 See the ICH guidance for industry Q9 Quality Risk Management (June 2006), available on the FDA guidance web 
page. 
5 See the ICH guidances for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug 
Substances and New Drug Products: Chemical Substances (December 2000) and Q6B Substances: Test Procedures 
and Acceptance Criteria for Biotechnological/Biological Products (August 1999), available on the FDA guidance 
web page. 
  2  Contains Nonbinding Recommendations 
 
77   
78  A.  Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral 
79  and Inhalation Routes of Administration (3.1) 
80   
81  The method used for establishing the PDE for each elemental impurity is discussed in detail in 
82  Appendix 1. Elements evaluated in this guidance were assessed by reviewing the publicly 
83  available data contained in scientific journals, government research reports and studies, 
84  international regulatory standards (applicable to drug products) and guidance, and regulatory 
85  authority research and assessment reports. This process follows the principles described in the ICH 
86  guidance for industry Q3C Impurities: Residual Solvents (December 2017) (ICH Q3C).6 The 
87  available information was reviewed to establish the oral, parenteral and inhalation PDEs. For 
88  practical purposes, the PDEs to be applied to the drug product that are presented in Appendix 2 
89  Table A.2.1 have been rounded to 1 or 2 significant figures. 
90   
91  A summary safety assessment identifying the critical study for setting a PDE for each element is 
92  included in Appendix 3. There are insufficient data to set PDEs by any route of administration 
93  for iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on 
94  the basis of their similarity to palladium. 
95   
96  The factors considered in the safety assessment for establishing the PDE are listed below in 
97  approximate order of relevance: 
98    The likely oxidation state of the element in the drug product 
99    Human exposure and safety data when it provided applicable information 
100    The most relevant animal study 
101    Route of administration 
102    The relevant endpoint(s) 
103   
104  Standards for daily intake for some of the elemental impurities discussed in this guidance exist for 
105  food, water, air, and occupational exposure. Where appropriate, these standards were considered 
106  in the safety assessment and establishment of the PDEs. 
107   
108  The longest duration animal study was generally used to establish the PDE. When a shorter 
109  duration animal study was considered the most relevant, the rationale was provided in the 
110  individual safety assessment. 
111   
112  Inhalation studies using soluble salts (when available) were preferred over studies using 
113  particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on 
114  available data, inhalation PDEs were based on either local (respiratory system) or systemic 
115  toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses 
116  were normalized to a 24-hour, 7-day exposure. 
117   
 
6 See the ICH guidance for industry Q3C Impurities: Residual Solvents (December 1997), available on the FDA web 
page at Q8, Q9 and Q10 Questions and Answers (R4). 
  3  Contains Nonbinding Recommendations 
 
118  In the absence of data and/or where data are available but not considered sufficient for a safety 
119  assessment for the parenteral and or inhalation route of administration, modifying factors based 
120  on oral bioavailability were used to derive the PDE from the oral PDE: 
121    Oral bioavailability <1%: divide by a modifying factor of 100 
122    Oral bioavailability  1% and <50%: divide by a modifying factor of 10 
123    Oral bioavailability 50% and <90%: divide by a modifying factor of 2 
124    Oral bioavailability  90%: divide by a modifying factor of 1 
125  Where oral bioavailability data or occupational inhalation exposure limits were not available, a 
126  calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1). 
127   
128  B.  Other Routes of Administration (3.2) 
129   
130  PDEs were established for oral, parenteral and inhalation routes of administration. In addition, 
131  PDEs for the cutaneous and transcutaneous route of administration are provided in Appendix 5. 
132  When PDEs are necessary for other routes of administration, the concepts described in this 
133  guidance may be used to derive PDEs. An assessment may either increase or decrease an 
134  established PDE. The process of derivation of the PDE for another route of administration may 
135  include the following: 
136    Consider the oral PDE in Appendix 3 as a starting point in developing a route-specific PDE. 
137  Based on a scientific evaluation, the parenteral and inhalation PDEs may be a more 
138  appropriate starting point. 
139    Assess if the elemental impurity is expected to have local effects when administered 
140  by the intended route of administration: 
141    If local effects are expected, assess whether a modification to an established PDE is 
o
142  necessary. 
143    Consider the doses/exposures at which these effects can be expected relative to 
o
144  the adverse effect that was used to set an established PDE. 
145    If local effects are not expected, no adjustment to an established PDE is necessary. 
o
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    When a difference is observed, a correction factor may be applied to an 
o
150  established PDE. For example, when no local effects are expected, if the oral 
151  bioavailability of an element is 50% and the bioavailability of an element by the 
152  intended route is 10%, a correction factor of 5 may be applied. 
153    If a PDE proposed for the new route is increased relative to an established PDE, 
154  quality attributes may need to be considered. 
155   
156  C.  Justification for Elemental Impurity Levels Higher Than an Established PDE 
157  (3.3) 
158   
  4  Contains Nonbinding Recommendations 
 
159  Levels of elemental impurities higher than an established PDE (see Table A.2.1) may be 
160  acceptable in certain cases. These cases could include, but are not limited to, the 
161  following situations: 
162    Intermittent dosing 
163    Short term dosing (i.e., 30 days or less) 
164    Specific indications (e.g., life-threatening, unmet medical needs, rare diseases) 
165  Examples of justifying an increased level of an elemental impurity using a subfactor 
166  approach of a modifying factor (Ref. 2,3) are provided below. Other approaches may 
167  also be used to justify an increased level. Any proposed level higher than an established 
168  PDE should be justified on a case-by- case basis. 
169  Example 1: Element X is present in an oral drug product. From the element X 
170  monograph in Appendix 3, a No-Observed-Adverse-Effect Level (NOAEL) of 1.1 
171  milligram (mg)/kilogram (kg)/day (d) was identified. Modifying factors F1-F5 have been 
172  established as 5, 10, 5, 1 and 1, respectively. Using the standard approach for modifying 
173  factors as described in Appendix 1, the PDE is calculated as follows: 
174  PDE = 1.1 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 220 g/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 g/day  
182  For practical purposes, this value is rounded to 400 g/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 g/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 g/day. 
193   
194  D.  Parenteral Products (3.4) 
195   
196  Parenteral drug products with maximum daily volumes up to two liters may use the 
197  maximum daily volume to calculate permissible concentrations from PDEs. For products 
198  whose daily volumes, as specified by labeling and/or established by clinical practice, may 
  5  Contains Nonbinding Recommendations 
 
199  exceed two liters (e.g., saline, dextrose, total parenteral nutrition, solutions for irrigation), 
200  a 2-liter volume may be used to calculate permissible concentrations from PDEs (Ref. 4). 
201   
202  IV.  ELEMENT CLASSIFICATION (4) 
203   
204  The elements included in this guidance have been placed into three classes based on their toxicity 
205  (PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived 
206  from several factors including: probability of use in pharmaceutical processes, probability of 
207  being a co-isolated impurity with other elemental impurities in materials used in pharmaceutical 
208  processes, and the observed natural abundance and environmental distribution of the element. For 
209  the purposes of this guidance, an element with low natural abundance refers to an element with a 
210  reported natural abundance of < 1 atom/106 atoms of silicon (Ref. 5). The classification scheme is 
211  intended to focus the risk assessment on those elements that are the most toxic but also have a 
212  reasonable probability of inclusion in the drug product (see Table 5.1). The elemental impurity 
213  classes are: 
214  Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in 
215  the manufacture of pharmaceuticals. Their presence in drug products typically comes from 
216  commonly used materials (e.g., mined excipients). Because of their unique nature, these four 
217  elements require evaluation during the risk assessment, across all potential sources of elemental 
218  impurities and routes of administration. The outcome of the risk assessment will determine those 
219  components that may require additional controls which may in some cases include testing for 
220  Class 1 elements. It is not expected that all components will require testing for Class 1 elemental 
221  impurities; testing should only be applied when the risk assessment identifies it as the appropriate 
222  control to ensure that the PDE will be met. 
223  Class 2: Elements in this class are generally considered as route-dependent human toxicants. 
224  Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood 
225  of occurrence in the drug product. 
226    Class 2A elements have relatively high probability of occurrence in the drug 
227  product and thus require risk assessment across all potential sources of 
228  elemental impurities and routes of administration (as indicated). The class 2A 
229  elements are: Co, Ni and V. 
230    Class 2B elements have a reduced probability of occurrence in the drug 
231  product related to their low abundance and low potential to be co-isolated with 
232  other materials. As a result, they may be excluded from the risk assessment 
233  unless they are intentionally added during the manufacture of drug substances, 
234  excipients, or other components of the drug product. The elemental impurities 
235  in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl. 
236   
237  Class 3: The elements in this class have relatively low toxicities by the oral route of administration 
238  (high PDEs, generally > 500 g/day) but may require consideration in the risk assessment for 
239  inhalation and parenteral routes. For oral routes of administration, unless these elements are 
240  intentionally added, they do not need to be considered during the risk assessment. For parenteral 
241  and inhalation products, the potential for inclusion of these elemental impurities should be 
  6  Contains Nonbinding Recommendations 
 
242  evaluated during the risk assessment, unless the route specific PDE is above 500 g/day. The 
243  elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn. 
244   
245  Other elements: Some elemental impurities for which PDEs have not been established due to 
246  their low inherent toxicity and/or differences in regional regulations are not addressed in this 
247  guidance. If these elemental impurities are present or included in the drug product they are 
248  addressed by other guidances and/or regional regulations and practices that may be applicable for 
249  particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with 
250  compromised hepatic function), or quality considerations (e.g., presence of W impurities in 
251  therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, 
252  Ca, Fe, K, Mg, Mn, Na, W and Zn. 
253   
254  V.  RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES (5) 
255   
256  In developing controls for elemental impurities in drug products, the principles of quality risk 
257  management, described in ICH Q9, should be considered. The risk assessment should be based 
258  on scientific knowledge and principles. It should link to safety considerations for patients with an 
259  understanding of the product and its manufacturing process (ICH Q8 and Q11). In the case of 
260  elemental impurities, the product risk assessment would therefore be focused on assessing the 
261  levels of elemental impurities in a drug product in relation to the PDEs presented in this 
262  guidance. Information for this risk assessment includes but is not limited to: data generated by 
263  the applicant, information supplied by drug substance and/or excipient manufacturers and/or data 
264  available in published literature. 
265  The applicant should document the risk assessment and control approaches in an appropriate 
266  manner. The level of effort and formality of the risk assessment should be proportional to the 
267  level of risk. It is neither always appropriate nor always necessary to use a formal risk 
268  management process (using recognized tools and/or formal procedures, e.g., standard operating 
269  procedures.) The use of informal risk management processes (using empirical tools and/or 
270  internal procedures) may also be considered acceptable. Tools to assist in the risk assessment are 
271  described in ICH Q8 and Q9 and will not be presented in this guidance. 
272   
273  A.  General Principles (5.1) 
274   
275  For the purposes of this guidance, the risk assessment process can be described in three steps: 
276    Identify known and potential sources of elemental impurities that may find their way 
277  into the drug product. 
278    Evaluate the presence of a particular elemental impurity in the drug product by 
279  determining the observed or predicted level of the impurity and comparing with the 
280  established PDE. 
281    Summarize and document the risk assessment. Identify if controls built into the 
282  process are sufficient or identify additional controls to be considered to limit 
283  elemental impurities in the drug product. 
  7  Contains Nonbinding Recommendations 
 
284  In many cases, the steps are considered simultaneously. The outcome of the risk assessment may 
285  be the result of iterations to develop a final approach to ensure the potential elemental impurities 
286  do not exceed the PDE. 
287   
288  B.  Potential Sources of Elemental Impurities (5.2) 
289   
290  In considering the production of a drug product, there are broad categories of potential sources of 
291  elemental impurities. 
292    Residual impurities resulting from elements intentionally added (e.g., catalysts) in the 
293  formation of the drug substance, excipients, or other drug product components. The 
294  risk assessment of the drug substance should address the potential for inclusion of 
295  elemental impurities in the drug product. 
296    Elemental impurities that are not intentionally added and are potentially present in the 
297  drug substance, water or excipients used in the preparation of the drug product. 
298    Elemental impurities that are potentially introduced into the drug substance and/or 
299  drug product from manufacturing equipment. 
300    Elemental impurities that have the potential to be leached into the drug substance and 
301  drug product from container closure systems. 
302  The following diagram shows an example of typical materials, equipment and components used 
303  in the production of a drug product. Each of these sources may contribute elemental impurities to 
304  the drug product, through any individual or any combination of the potential sources listed 
305  above. During the risk assessment, the potential contributions from each of these sources should be 
306  considered to determine the overall contribution of elemental impurities to the drug product. 
307     
  8  Contains Nonbinding Recommendations 
 
308   
Manufacturing  Drug 
equipment * Substance
Elemental 
impurities 
in drug 
Product
Water ** Container  Excipients
Closure 
 
System
309   
310     
311  * The risk of inclusion of elemental impurities can be reduced through process understanding, equipment 
312  selection, equipment qualification and Good Manufacturing Practice (GMP) processes. 
313  ** The risk of inclusion of elemental impurities from water can be reduced by complying with compendial 
314  (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water quality 
315  requirements, if purified water or water for injection is used in the manufacturing process(es). 
316   
317  C.  Identification of Potential Elemental Impurities (5.3) 
318   
319  Potential elemental impurities derived from intentionally added catalysts and inorganic 
320  reagents: If any element listed in Table 5.1 is intentionally added, it should be considered in the 
321  risk assessment. For this category, the identity of the potential impurities is known and 
322  techniques for controlling the elemental impurities are easily characterized and defined. 
323  Potential elemental impurities that may be present in drug substances and/or excipients: 
324  While not intentionally added, some elemental impurities may be present in some drug 
325  substances and/or excipients. The possibility for inclusion of these elements in the drug product 
326  should be reflected in the risk assessment. 
327  For the oral route of administration, the risk assessment should evaluate the possibility for 
328  inclusion of Class 1 and Class 2A elemental impurities in the drug product. For parenteral and 
329  inhalation routes of administration, the risk assessment should evaluate the possibility for 
330  inclusion of the Class 1, Class 2A and Class 3 elemental impurities as shown in Table 5.1. 
331  Potential elemental impurities derived from manufacturing equipment: The contribution of 
332  elemental impurities from this source may be limited and the subset of elemental impurities that 
333  should be considered in the risk assessment will depend on the manufacturing equipment used in 
334  the production of the drug product. Application of process knowledge, selection of equipment, 
335  equipment qualification and GMP controls ensure a low contribution from manufacturing 
  9  Contains Nonbinding Recommendations 
 
336  equipment. The specific elemental impurities of concern should be assessed based on knowledge 
337  of the composition of the components of the manufacturing equipment that come in contact with 
338  components of the drug product. The risk assessment of this source of elemental impurities is 
339  one that can potentially be utilized for many drug products using similar process trains and 
340  processes. 
341  In general, the processes used to prepare a given drug substance are considerably more 
342  aggressive than processes used in preparing the drug product when assessed relative to the 
343  potential to leach or remove elemental impurities from manufacturing equipment. Contributions 
344  of elemental impurities from drug product processing equipment would be expected to be lower 
345  than contributions observed for the drug substance. However, when this is not the case based on 
346  process knowledge or understanding, the applicant should consider the potential for 
347  incorporation of elemental impurities from the drug product manufacturing equipment in the risk 
348  assessment (e.g., hot melt extrusion). 
349  Elemental impurities leached from container closure systems: The identification of potential 
350  elemental impurities that may be introduced from container closure systems should be based on a 
351  scientific understanding of likely interactions between a particular drug product type and its 
352  packaging. When a review of the materials of construction demonstrates that the container 
353  closure system does not contain elemental impurities, no additional risk assessment needs to be 
354  performed. It is recognized that the probability of elemental leaching into solid dosage forms is 
355  minimal and does not require further consideration in the risk assessment. For liquid and semi-
356  solid dosage forms there is a higher probability that elemental impurities could leach from the 
357  container closure system during the shelf-life of the product. Studies to understand potential 
358  leachables from the container closure system (after washing, sterilization, irradiation, etc.) 
359  should be performed. This source of elemental impurities will typically be addressed during 
360  evaluation of the container closure system for the drug product. 
361  Factors that should be considered (for liquid and semi-solid dosage forms) include but 
362  are not limited to: 
363    Hydrophilicity/hydrophobicity 
364    Ionic content 
365    pH 
366    Temperature (cold chain vs room temperature and processing conditions) 
367    Contact surface area 
368    Container/component composition 
369    Terminal sterilization 
370    Packaging process 
371    Component sterilization 
372    Duration of storage 
373   
374  D.  Recommendations for Elements to be Considered in the Risk Assessment (5.4) 
375   
376  The following table provides recommendations for inclusion of elemental impurities in the risk 
377  assessment. This table can be applied to all sources of elemental impurities in the drug product. 
  10  Contains Nonbinding Recommendations 
 
378   
379  Table V.1 (5.1): Elements to be Considered in the Risk Assessment 
Element  Class  If intentionally  If not intentionally added 
added (all routes) 
      Oral  Parenteral  Inhalation 
Cd  1  yes  yes  yes  yes 
Pb  1  yes  yes  yes  yes 
As  1  yes  yes  yes  yes 
Hg  1  yes  yes  yes  yes 
Co  2A  yes  yes  yes  yes 
V  2A  yes  yes  yes  yes 
Ni  2A  yes  yes  yes  yes 
Tl  2B  yes  no  no  no 
Au  2B  yes  no  no  no 
Pd  2B  yes  no  no  no 
Ir  2B  yes  no  no  no 
Os  2B  yes  no  no  no 
Rh  2B  yes  no  no  no 
Ru  2B  yes  no  no  no 
Se  2B  yes  no  no  no 
Ag  2B  yes  no  no  no 
Pt  2B  yes  no  no  no 
Li  3  yes  no  yes  yes 
Sb  3  yes  no  yes  yes 
Ba  3  yes  no  no  yes 
Mo  3  yes  no  no  yes 
Cu  3  yes  no  yes  yes 
Sn  3  yes  no  no  yes 
Cr  3  yes  no  no  yes 
380   
381  E.  Evaluation (5.5) 
382   
383  As the potential elemental impurity identification process is concluded, there are two possible 
384  outcomes: 
385  1) The risk assessment process does not identify any potential elemental impurities. The 
386  conclusion of the risk assessment and supporting information and data should be 
387  documented. 
388  2) The risk assessment process identifies one or more potential elemental impurities. For 
389  any elemental impurities identified in the process, the risk assessment should consider 
390  if there are multiple sources of the identified elemental impurity or impurities and 
391  document the conclusion of the assessment and supporting information. 
392  The applicants risk assessment can be facilitated with information about the potential elemental 
393  impurities provided by suppliers of drug substances, excipients, container closure systems, and 
394  manufacturing equipment. The data that support this risk assessment can come from a number of 
395  sources that include, but are not limited to: 
396    Prior knowledge 
  11  Contains Nonbinding Recommendations 
 
397    Published literature 
398    Data generated from similar processes 
399    Supplier information or data 
400    Testing of the components of the drug product 
401    Testing of the drug product 
402  During the risk assessment, a number of factors that can influence the level of the potential 
403  impurity in the drug product and should also have been considered in the risk assessment. These 
404  include but are not limited to: 
405    Efficiency of removal of elemental impurities during further processing 
406    Natural abundance of elements (especially important for the categories of 
407  elements which are not intentionally added) 
408    Prior knowledge of elemental impurity concentration ranges from specific 
409  sources 
410    The composition of the drug product 
411   
412  F.  Summary of Risk Assessment Process (5.6) 
413   
414  The risk assessment is summarized by reviewing relevant product or component specific data 
415  combined with information and knowledge gained across products or processes to identify the 
416  significant probable elemental impurities that may be observed in the drug product. 
417  The summary should consider the significance of the observed or predicted level of the elemental 
418  impurity relative to the PDE of the elemental impurity. As a measure of the significance of the 
419  observed elemental impurity level, a control threshold is defined as a level that is 30% of the 
420  established PDE in the drug product. The control threshold may be used to determine if additional 
421  controls are warranted.  
422   
423  If the total elemental impurity level from all sources in the drug product is expected to be 
424  consistently less than 30% of the PDE, then additional controls are not required, provided the 
425  applicant has appropriately assessed the data and demonstrated adequate controls on elemental 
426  impurities. 
427   
428  If the risk assessment fails to demonstrate that an elemental impurity level is consistently less 
429  than the control threshold, controls should be established to ensure that the elemental impurity 
430  level does not exceed the PDE in the drug product. (See section VI (6).) 
431   
432  The variability of the level of an elemental impurity should be factored into the application of the 
433  control threshold to drug products. Sources of variability may include: 
434    Variability of the analytical method 
435    Variability of the elemental impurity level in the specific sources 
436    Variability of the elemental impurity level in the drug product 
437   
438  At the time of submission, in the absence of other justification, the level and variability of an 
439  elemental impurity can be established by providing the data from three (3) representative 
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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 
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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 (g/day) provided in this document give the 
504  maximum permitted quantity of each element that may be contained in the maximum daily intake 
505  of a drug product. Because the PDE reflects only total exposure from the drug product, it is useful 
506  to convert the PDE, into concentrations as a tool in evaluating elemental impurities in drug 
507  products or their components. The options listed in this section describe some acceptable 
508  approaches to establishing concentrations of elemental impurities in drug products or 
509  components that would assure that the drug product does not exceed the PDEs. The applicant 
510  may select any of these options as long as the resulting permitted concentrations assure that the 
511  drug product does not exceed the PDEs. In the choice of a specific option the applicant must have 
512  knowledge of, or make assumptions about, the daily intake of the drug product. The permitted 
513  concentration limits may be used: 
514    As a tool in the risk assessment to compare the observed or predicted levels to the PDE 
515    In discussions with suppliers to help establish upstream controls that would assure 
516  that the product does not exceed the PDE 
517    To establish concentration targets when developing in-process controls on elemental 
518  impurities 
519    To convey information regarding the controls on elemental impurities in regulatory 
520  submissions 
521   
522  As discussed in section V.B (5.2), there are multiple sources of elemental impurities in drug 
523  products. When applying any of the options described below, elemental impurities from 
524  container closure systems and manufacturing equipment should be taken into account before 
525  calculating the maximum permitted concentration in the remaining components (excipients and 
526  drug substance). If it is determined during the risk assessment that the container closure systems 
527  and manufacturing equipment do not contribute to the elemental impurity level in the drug 
  14  Contains Nonbinding Recommendations 
 
528  product, they do not need to be considered. Where contributions from container closure systems 
529  and manufacturing equipment exist, these contributions may be accounted for by subtracting the 
530  estimated daily intake from these sources from the PDE before calculation of the allowed 
531  concentration in the excipients and drug substance.  
532   
533  Option 1: Common permitted concentration limits of elements across drug product 
534  components for drug products with daily intakes of not more than 10 grams: 
535   
536  This option is not intended to imply that all elements are present at the same concentration, but 
537  rather provides a simplified approach to the calculations. 
538   
539  The option assumes the daily intake (amount) of the drug product is 10 grams or less, and that 
540  elemental impurities identified in the risk assessment (the target elements) are present in all 
541  components of the drug product. Using Equation 1 below, and a daily intake of ten grams of drug 
542  product, this option calculates a common permissible target elemental concentration for each 
543  component in the drug. This approach, for each target element, allows determination of a fixed 
544  common maximum concentration in micrograms per gram in each component. The permitted 
545  concentrations are provided in Appendix 2, Table A.2.2.  
546         
PDE(g/day)
547    Concentration(g/ g) =     (1) 
daily amount of drug product(g/day)
548   
549  If all the components in a drug product do not exceed the Option 1 concentrations for all target 
550  elements identified in the risk assessment, then all these components may be used in any 
551  proportion in the drug product. An example using this option is shown in Appendix 4, Table 
552  A.4.2. If the permitted concentrations in Appendix 2, Table A.2.2 are not applied, Options 2a, 2b, 
553  or 3 should be followed. 
554   
555  Option 2a: Common permitted concentration limits across drug product components for a 
556  drug product with a specified daily intake: 
557   
558  This option is similar to Option 1, except that the drug daily intake is not assumed to be 10 
559  grams. The common permitted concentration of each element is determined using Equation 1 and 
560  the actual maximum daily intake. 
561  This approach, for each target element, allows determination of a fixed common maximum 
562  concentration in micrograms per gram in each component based on the actual daily intake 
563  provided. An example using this option is provided in Appendix 4, Table A.4.3. 
564  If all components in a drug product do not exceed the Option 2a concentrations for all target 
565  elements identified in the risk assessment, then all these components may be used in any 
566  proportion in the drug product. 
567   
568  Option 2b: Permitted concentration limits of elements in individual components of a 
569  product with a specified daily intake: 
570   
  15  Contains Nonbinding Recommendations 
 
571  This option requires additional information that the applicant may assemble regarding the 
572  potential for specific elemental impurities to be present in specific drug product components. The 
573  applicant may set permitted concentrations based on the distribution of elements in the 
574  components (e.g., higher concentrations in components with the presence of an element in 
575  question). For each element identified as potentially present in the components of the drug 
576  product, the maximum expected mass of the elemental impurity in the final drug product can be 
577  calculated by multiplying the mass of each component material times the permitted concentration 
578  established by the applicant in each material and summing over all components in the drug 
579  product, as described in Equation 2. The total mass of the elemental impurity in the drug product 
580  should comply with the PDEs given in Appendix 2, Table A.2.1. unless justified according to 
581  other relevant sections of this guidance. If the risk assessment has determined that a specific 
582  element is not a potential impurity in a specific component, there is no need to establish a 
583  quantitative result for that element in that component. This approach allows that the maximum 
584  permitted concentration of an element in certain components of the drug product may be higher 
585  than the Option 1 or Option 2a limit, but this should then be compensated by lower allowable 
586  concentrations in the other components of the drug product. Equation 2 may be used to 
587  demonstrate that component-specific limits for each element in each component of a drug 
588  product assure that the PDE will be met. 
589   
N
590  PDE(g day) C M     (2) 
k k
k=1
591   
592  k =  an index for each of N components in the drug product 
593  C =  permitted concentration of the elemental impurity in component k (g/g)  
k 
594  M =   mass of component k in the maximum daily intake of the drug product (g) 
k 
595   
596  An example using this option is provided in Appendix 4 Tables A.4.4  A.4.5. 
597   
598  Option 3: Finished Product Analysis: 
599  The concentration of each element may be measured in the final drug product. Equation 1 may 
600  be used with the maximum total daily dose of the drug product to calculate a maximum permitted 
601  concentration of the elemental impurity. An example using this option is provided in Appendix 4, 
602  Table A.4.6. 
603   
604  VIII.  Speciation and Other Considerations (8) 
605   
606  Speciation is defined as the distribution of elements among chemical species including isotopic 
607  composition, electronic or oxidation state, and/or complex or molecular structure. When the 
608  toxicities of different species of the same element are known, the PDE has been established using 
609  the toxicity information on the species expected to be in the drug product. 
610  When elemental impurity measurements are used in the risk assessment, total elemental impurity 
611  levels in drug products may be used to assess compliance with the PDEs. The applicant is not 
612  expected to provide speciation information; however, such information could be used to justify 
613  lower or higher levels when the identified species is more or less toxic, respectively, than the 
614  species used in the monographs in Appendix 3. 
  16  Contains Nonbinding Recommendations 
 
615  When total elemental impurity levels in components are used in the risk assessment, the applicant 
616  is not expected to provide information on release of an elemental impurity from the component 
617  in which it is found. However, such information could be used to justify levels higher than those 
618  based on the total elemental impurity content of the drug product. 
619   
620  IX.  Analytical Procedures (9) 
621   
622  The determination of elemental impurities should be conducted using appropriate procedures 
623  suitable for their intended purposes. Unless otherwise justified, the test should be specific for 
624  each elemental impurity identified for control during the risk assessment. Pharmacopoeial 
625  procedures or suitable alternative procedures for determining levels of elemental impurities 
626  should be used. 
627   
628  X.  Lifecycle Management (10) 
629   
630  The quality systems and management responsibilities described in ICH guidance for industry 
631  Q10 Pharmaceutical Quality System (April 2009) (ICH Q10)7 are intended to encourage the use 
632  of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual 
633  improvement across the entire product lifecycle. Product and process knowledge should be 
634  managed from development through the commercial life of the product up to and including 
635  product discontinuation. 
636  Knowledge gained from development combined with commercial manufacturing experience and 
637  data can be used to further improve process understanding and process performance. Such 
638  improvements can enhance controls on elemental impurities. It is recognized that the elemental 
639  impurity data available for some components is somewhat limited at the date of publication of 
640  this guidance, which may direct the applicant to a specific set of controls. Additional data, if 
641  developed, may lead to modifications of the controls. 
642   
643  If changes to the drug product or components have the potential to change the elemental impurity 
644  content of the drug product, the risk assessment, including established controls for elemental 
645  impurities, should be re-evaluated. Such changes could include, but are not limited to: changes in 
646  synthetic routes, excipient suppliers, raw materials, processes, equipment, container closure 
647  systems or facilities. All changes are subject to internal change management process (ICH 
648  Q10) and if needed appropriate regional regulatory requirements.  
649   
 
7 The ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009) is available on the FDA guidance 
web page. 
  17  Contains Nonbinding Recommendations 
 
650  GLOSSARY 
651  ACGIH:  American Conference of Governmental Industrial Hygienists. 
652  ATSDR:  Agency for Toxic Substances and Disease Registry. 
653  CEC:  Commission of the European Community. 
654  CFR:  Code of Federal Regulations. (USA) 
655  Change Management:  A systematic approach to proposing, evaluating, approving, 
656  implementing, and reviewing changes. (ICH Q10) 
657  CICAD:  Concise International Chemical Assessment Documents. (WHO) 
658  Container Closure System:  The sum of packaging components that together contain 
659  and protect the dosage form. This includes primary packaging components and 
660  secondary packaging components, if the latter are intended to provide additional 
661  protection to the drug product. A packaging system is equivalent to a container 
662  closure system. (ICH Q1A) 
663  Control Strategy:  A planned set of controls, derived from current product and 
664  process understanding, that assures process performance and product quality. The 
665  controls can include parameters and attributes related to drug substance and drug 
666  product materials and components, facility and equipment operating conditions, in- 
667  process controls, finished product specifications, and the associated methods and 
668  frequency of monitoring and control. (ICH Q10) 
669  Control Threshold:  A limit that is applied during the assessment of elemental 
670  impurities to determine if additional control elements may be required to ensure that 
671  the PDE is not exceeded in the drug product. The limit is defined as 30% of the PDE 
672  of the specific elemental impurity under consideration. 
673  Daily Dose:  The total mass of drug product that is consumed by a patient on a daily 
674  basis. 
675  EFSA:  European Food Safety Agency. 
676  EHC:  Environmental Health Criteria. (IPCS, WHO) 
677  EU SCOEL:  European Scientific Committee on Occupational Exposure Limits. 
678  EU SEG:  European Union Scientific Expert Group. 
679  Herbal Products:  Medicinal products containing, exclusively, plant material and/or 
680  vegetable drug preparations as active ingredients. In some traditions, materials of 
681  inorganic or animal origin can also be present. 
682  IARC:  International Agency for Research on Cancer. 
683  Inhalation Unit Risk:  The upper-bound excess lifetime cancer risk estimated to result 
684  from continuous exposure to an agent at a concentration of 1 g/L in water, or 1 
3 
685  g/m in air. The interpretation of inhalation unit risk would be as follows: if unit risk 
  18  Contains Nonbinding Recommendations 
 
-6 
686  = 2 x 10 per g/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 g of the chemical in 
688  1 liter of drinking water. (US EPA) 
689  IPCS:  International Programme for Chemical Safety. 
690  IUPAC:  International Union of Pure and Applied Chemistry. 
691  IRIS:  Integrated Risk Identification System, United States Environmental Protection 
692  Agency. 
693  LOAEL:  Lowest-Observed-Adverse-Effect Level: Lowest concentration or amount 
694  of a substance (dose), found by experiment or observation, that causes an adverse 
695  effect on morphology, functional capacity, growth, development, or life span of a 
696  target organism distinguishable from normal (control) organisms of the same species 
697  and strain under defined conditions of exposure. (IUPAC) 
698  LoQ:  Limit of Quantitation: The quantitation limit of an individual analytical 
699  procedure is the lowest amount of analyte in a sample which can be quantitatively 
700  determined with suitable precision and accuracy. The quantitation limit is a parameter 
701  of quantitative assays for low levels of compounds in sample matrices, and is used 
702  particularly for the determination of impurities and/or degradation products. (ICH Q2) 
703  LOEL:  Lowest-Observed-Effect Level: The lowest dose of substance in a study or 
704  group of studies that produces biologically significant increases in frequency or 
705  severity of any effects in the exposed humans or animals. 
706  Modifying Factor:  An individual factor determined by professional judgment of a 
707  toxicologist and applied to bioassay data to relate that data to human safety. (ICH 
708  Q3C) (See related term Safety Factor) 
709  MRL:  Minimal Risk Level: An estimate of the daily human exposure to a hazardous 
710  substance that is likely to be without appreciable risk. (ATSDR) 
711  NAS:  National Academy of Science. (USA) 
712  NOAEL:  No-Observed-Adverse-Effect Level: Greatest concentration or amount of a 
713  substance, found by experiment or observation, that causes no detectable adverse 
714  alteration of morphology, functional capacity, growth, development, or life span of the 
715  target organism under defined conditions of exposure. 
716  NOEL:  No-Observed-Effect Level: The highest dose of substance at which there are 
717  no biologically significant increases in frequency or severity of any effects in the 
718  exposed humans or animals. 
719  NTP:  National Toxicology Program. (USA) 
720  OEHHA:  Office of Environmental Health Hazard Assessment. (California, USA) 
721  OELV:  Occupational Exposure Limit Value. 
722  OSHA:  Occupational Safety and Health Administration. (USA) 
  19  Contains Nonbinding Recommendations 
 
723  PEL:  Permitted Exposure Limit. 
724  PDE:  Permitted Daily Exposure: The maximum acceptable intake of elemental 
725  impurity in pharmaceutical products per day. 
726  Product Lifecycle:  All phases in the life of the product from the initial development 
727  through marketing until the products discontinuation. (ICH Q9) 
728  Quality:  The degree to which a set of inherent properties of a product, system, or 
729  process fulfills requirements (see ICH Q6A definition specifically for quality of drug 
730  substance and drug products). (ICH Q9) 
731  Quality Risk Management:  A systematic process for the assessment, control, 
732  communication, and review of risks to the quality of the drug product across the 
733  product lifecycle. (ICH Q9) 
734  Quality System:  The sum of all aspects of a system that implements quality policy 
735  and ensures that quality objectives are met. (ICH Q10) 
736  Risk:  The combination of the probability of occurrence of harm and the severity of 
737  that harm. (ISO/IEC Guide 51, ICH Q9) 
738  Risk Acceptance:  The decision to accept risk. (ISO Guide 73) 
739  Risk Analysis:  The estimation of the risk associated with the identified hazards. (ICH 
740  Q9) 
741  Risk Assessment:  A systematic process of organizing information to support a risk 
742  decision to be made within a risk management process. It consists of the identification 
743  of hazards and the analysis and evaluation of risks associated with exposure to those 
744  hazards. (ICH Q9) 
745  Risk Control:  Actions implementing risk management decisions. (ISO Guide 73) 
746  Risk Identification:  The systematic use of information to identify potential sources 
747  of harm (hazards) referring to the risk question or problem description. (ICH Q9) 
748  Risk Management:  The systematic application of quality management policies, 
749  procedures, and practices to the tasks of assessing, controlling, communicating, and 
750  reviewing risk. (ICH Q9) 
751  Safety:  Practical certainty that adverse effects will not result from exposure to an 
752  agent under defined circumstances (Ref. 2). 
753  Safety Assessment:  An approach that focuses on the scientific understanding and 
754  measurement of chemical hazards as well as chemical exposures, and ultimately the 
755  risks associated with them. This term is often (and in this guidance) used 
756  synonymously with risk assessment (Ref. 2). 
757  Safety Factor:  A composite (reductive) factor applied by the risk assessment experts 
758  to the NOAEL or other reference point, such as the benchmark dose or benchmark 
759  dose lower confidence limit, to derive a reference dose that is considered safe or 
760  without appreciable risk, such as an acceptable daily intake or tolerable daily intake 
  20  Contains Nonbinding Recommendations 
 
761  (the NOAEL or other reference point is divided by the safety factor to calculate the 
762  reference dose). The value of the safety factor depends on the nature of the toxic 
763  effect, the size and type of population to be protected, and the quality of the 
764  toxicological information available. See related terms: Assessment factor, Uncertainty 
765  factor (Ref. 2). 
766  Severity:  A measure of the possible consequences of a hazard. (ICH Q9) 
767  TLV:  Threshold Limit Value: The concentration in air to which it is believed that most 
768  workers can be exposed daily without an adverse effect (i.e., effectively, the threshold 
769  between safe and dangerous concentrations). The values were established (and are 
770  revised annually) by the ACGIH and are time- weighted concentrations (TWA) for a 
771  7- or 8-hour workday and 40-hour workweek, and thus related to chronic effects. 
772  (IUPAC) 
773  TWA:  Time Weighted Average: As defined by ACGIH, time-weighted average 
774  concentration for a conventional 8-hour workday and a 40-hour workweek. (IUPAC) 
775  URF:  Unit Risk Factor. 
776  US DoL:  United States Department of Labor. 
777  US EPA:  United States Environmental Protection Agency. 
778  WHO:  World Health Organization. 
779     
  21  Contains Nonbinding Recommendations 
 
780  REFERENCES 
781   
782  1.  Ball D, Blanchard J, Jacobson-Kram D, McClellan R, McGovern T, Norwood DL et al. 
783  2007, Development of safety qualification thresholds and their use in orally inhaled and 
784  nasal drug product evaluation, Toxicol Sci, 97(2):226-36.  
785  2.  IPCS. Principles and methods for the risk assessment of chemicals in food, chapter 5: dose-
786  response assessment and derivation of health based guidance values, 2009, Environmental 
787  Health  Criteria  240,  International  Programme  on  Chemical  Safety.  World  Health 
788  Organization, Geneva, Table 5.5. 
789  3.  US EPA. 0410 Boron and Compounds, 2004, Integrated Risk Management System (IRIS). 
790  4.  Holliday MA, Segar WE, 1957, The maintenance need for water in parenteral fluid therapy, 
791  Pediatrics, 19:823-32. 
792  5.  Haxel GB, Hedrick JB, Orris GJ, 2005, Rare earth elements-critical resources for high 
793  technology, US Geological Survey, Fact Sheet 087-02.
  22  Contains Nonbinding Recommendations 
 
794  Appendix 1: Method for Establishing Exposure Limits 
795   
796  For most elements, acceptable exposure levels for elemental impurities in this guidance were 
797  established by calculation of PDE values according to the procedures for setting exposure limits 
798  in pharmaceuticals (Ref. 1), and the method adopted by International Programme for Chemical 
799  Safety (IPCS) for Assessing Human Health Risk of Chemicals (Ref. 2). These methods are 
800  similar to those used by the United States Environmental Protection Agency (US EPA) Integrated 
801  Risk Information System, the United States Food and Drug Administration (US FDA) (Ref. 3) 
802  and others. The method is outlined here to give a better understanding of the origin of the PDE 
803  values. When an MRL was used to set the PDE, no additional modifying factors were used as 
804  they are incorporated into the derivation of the MRL. For carcinogenic elements unit risk factors 
805  were used to set the PDE using a 1:100000 risk level; these are described in the individual 
806  monographs in Appendix 3. Some PDEs for inhalation were derived using occupational exposure 
807  limits, applying modifying factors, and considering any specific effects to the respiratory system. 
808  The PDE is derived from the No-Observed-Effect Level (NO[A]EL), or the Lowest-
809  Observed-Effect Level (LO[A]EL) in the most relevant animal study as follows: 
810   
811  PDE = NO(A)EL x Mass Adjustment/[F1 x F2 x F3 x F4 x F5]  (A.1.1) 
812   
813  The PDE is derived preferably from a NO(A)EL. If no NO(A)EL is obtained, the LO(A)EL may 
814  be used. Modifying factors proposed here, for relating the data to humans, are the same kind of 
815  "uncertainty factors" used in Environmental Health Criteria (Ref. 2), and "modifying factors" or 
816  "safety factors" in Pharmacopeial Forum. 
817   
818  The modifying factors are as follows: 
819   
820  F1 = A factor to account for extrapolation between species  
821  F1 = 1 for human data 
822  F1 = 5 for extrapolation from rats to humans  
823  F1 = 12 for extrapolation from mice to humans  
824  F1 = 2 for extrapolation from dogs to humans 
825  F1 = 2.5 for extrapolation from rabbits to humans  
826  F1 = 3 for extrapolation from monkeys to humans 
827  F1 = 10 for extrapolation from other animals to humans 
828  F1 takes into account the comparative surface area: body mass ratios for the species concerned 
829  and for man. Surface area (S) is calculated as: 
830   
831  S = kM0.67  (A.1.2) 
832   
833  in which M = body mass, and the constant k has been taken to be 10. The body masses used in 
834  Equation A.1.2 are those shown below in Table A.1.1. 
835  F2 = A factor of 10 to account for variability between individuals 
  23  Contains Nonbinding Recommendations 
 
836  A factor of 10 is generally given for all elemental impurities, and 10 is used consistently in this 
837  guidance  
838  F3 = A variable factor to account for toxicity studies of short-term exposure 
839  F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, 
840  dogs and monkeys) 
841  F3 = 1 for reproductive studies in which the whole period of organogenesis is covered  
842  F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents 
843  F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents  
844  F3 = 10 for studies of a shorter duration 
845  In all cases, the higher factor has been used for study durations between the time points, e.g., a 
846  factor of 2 for a 9-month rodent study. 
847  F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic carcinogenicity, 
848  neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following factors are used: 
849  F4 = 1 for fetal toxicity associated with maternal toxicity F4 = 5 for fetal toxicity without 
850  maternal toxicity 
851  F4 = 5 for a teratogenic effect with maternal toxicity 
852  F4 = 10 for a teratogenic effect without maternal toxicity 
853  F5 = A variable factor that may be applied if the NOEL was not established F5 = 1 for a NOEL 
854  F5 = 1-5 for a NOAEL F5 = 5-10 for a LOEL 
855  F5 = 10 for a Lowest-Observed-Adverse-Effect Level (LOAEL) 
856  For most elements the NOAEL was used to set the oral PDE, using a F5 of 1, as the studies did 
857  not investigate the difference between a NOAEL and NOEL and the toxicities were not considered 
858  adverse at the dose selected for determining the PDE. 
859  The mass adjustment assumes an arbitrary adult human body mass for either sex of 50 kg. This 
860  relatively low mass provides an additional safety factor against the standard masses of 60 kg or 70 
861  kg that are often used in this type of calculation. It is recognized that some patients weigh less 
862  than 50 kg; these patients are considered to be accommodated by the built-in safety factors used 
863  to determine a PDE and that lifetime studies were often used. For lead, the pediatric population is 
864  considered the most sensitive population, and data from this population were used to set the PDE. 
865  Therefore, the PDEs are considered appropriate for pharmaceuticals intended for pediatric 
866  populations. 
867  As an example of the application of Equation A.1.1, consider a toxicity study of cobalt in human 
868  volunteers as summarized in Tvermoes (Ref. 4). The NOAEL for polycythemia is 1 mg/day. The 
869  PDE for cobalt in this study is calculated as follows: 
870  PDE = 1 mg/day /(1 x 10 x 2 x 1 x 1) = 0.05 mg/day= 50 g/day  
871  In this example, 
872  F1 = 1 study in humans 
873  F2 = 10 to account for differences between individual humans  
874  F3 = 2 because the duration of the study was 90 days 
  24  Contains Nonbinding Recommendations 
 
875  F4 = 1 because no severe toxicity was encountered  
876  F5 = 1 because a NOAEL was used 
877   
878  Table A.1.1: Values Used in the Calculations in this Document 
Rat body weight  425 g  Mouse respiratory volume  43 L/day 
Pregnant rat body weight  330 g  Rabbit respiratory volume  1440 L/day 
Mouse body weight  28 g  Guinea pig respiratory volume  430 L/day 
Pregnant mouse body weight  30 g  Human respiratory volume  28,800 L/day 
Guinea pig body weight  500 g  Dog respiratory volume  9,000 L/day 
Rhesus monkey body weight  2.5 kg  Monkey respiratory volume  1,150 L/day 
Rabbit body weight  4 kg  Mouse water consumption  5 mL/day 
(pregnant or not) 
Beagle dog body weight  11.5 kg  Rat water consumption  30 mL/day 
Rat respiratory volume  290 L/day  Rat food consumption  30 g/day 
879   
880   
881  References 
882   
883  United States Pharmacopeial Convention, Pharmacopeial Forum, Nov-Dec 1989. 
884  IPCS. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health-
885  based Exposure Limits, Environmental Health Criteria 170. International Programme on 
886  Chemical Safety. World Health Organization, Geneva. 1994. 
887  US FDA, Guidance for Industry and Other Stakeholders: Toxicological Principles for the Safety 
888  Assessment of Food Ingredients (Redbook 2000), available at 
889  http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInform 
890  ation/IngredientsAdditivesGRASPackaging/ucm2006826.htm. 
891  Tvermoes BE, Unice KM, Paustenbach DJ, Finley BL, Otani JM, Galbraith DA. 2014, Effects 
892  and blood concentrations of cobalt after ingestion of 1 mg/d by human volunteers for 90 d. Am J 
893  Clin Nutr, 99:632-46. 
894   
895     
  25  Contains Nonbinding Recommendations 
 
896  Appendix 2: Established PDEs for Elemental Impurities 
897   
898  Table A.2.1: Permitted Daily Exposures for Elemental Impurities1 
899 
 
Element  Class2  Oral PDE,  Parenteral PDE,  Inhalation PDE, 
g/day  g/day  g/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 (g/day) have been established on the basis of safety data described in the 
901  monographs in Appendix 3, and apply to new drug products. The PDEs in the monographs are not rounded. 
902  For practical purposes the PDEs in this table have been rounded to 1 or 2 significant figures. PDEs less than 
903  10 have 1 significant figure and are rounded to the nearest unit. PDEs greater than 10 are rounded to 1 or 2 
904  significant figures as appropriate. The principles applied to rounding in this table may be applied to PDEs 
905  derived for other routes of administration. 
906  2 Classification as defined in section IV (4).
  26  Contains Nonbinding Recommendations 
 
907  Table A.2.2: Permitted Concentrations of Elemental Impurities for Option 1 
908  The values presented in this table represent permitted concentrations in micrograms per gram for 
909  elemental impurities in drug products, drug substances and excipients. These concentration 
910  limits are intended to be used when Option 1 is selected to assess the elemental impurity content 
911  in drug products with daily doses of not more than 10 grams per day. The numbers in this table 
912  are based on Table A.2.1. 
913 
 
Element  Class  Oral Concentration  Parenteral  Inhalation 
g/g  Concentration  Concentration 
g/g  g/g 
Cd  1  0.5  0.2  0.3 
Pb  1  0.5  0.5  0.5 
As  1  1.5  1.5  0.2 
Hg  1  3  0.3  0.1 
Co  2A  5  0.5  0.3 
V  2A  10  1  0.1 
Ni  2A  20  2  0.6 
Tl  2B  0.8  0.8  0.8 
Au  2B  30  30  0.3 
Pd  2B  10  1  0.1 
Ir  2B  10  1  0.1 
Os  2B  10  1  0.1 
Rh  2B  10  1  0.1 
Ru  2B  10  1  0.1 
Se  2B  15  8  13 
Ag  2B  15  1.5  0.7 
Pt  2B  10  1  0.1 
Li  3  55  25  2.5 
Sb  3  120  9  2 
Ba  3  140  70  30 
Mo  3  300  150  1 
Cu  3  300  30  3 
Sn  3  600  60  6 
Cr  3  1100  110  0.3 
914   
915     
  27  Contains Nonbinding Recommendations 
 
916  Appendix 3: Individual Safety Assessments  
917   
918  ANTIMONY 
919   
920  Summary of PDE for Antimony 
Antimony (Sb) 
  Oral  Parenteral  Inhalation 
PDE (g/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 Sb O was not 
2 3 
946  carcinogenic and propose that in previous studies, positive for carcinogenicity, the tumors may 
947  be the result of overload with insoluble particulates (Newton et al, 1994; WHO, 2003). 
948   
949  PDE  Oral Exposure 
950  Limited oral data on antimony exposure is available in mice and rats (Schroeder et al., 1968; 
951  Schroeder et al, 1970; Poon et al, 1998). The National Toxicology Program (NTP) conducted a 
952  14-day study in rats and mice where APT was administered in the drinking water. In this study 
953  APT was found to be relatively nontoxic by this route (NTP, 1992). Reevaluating the data of 
954  Poon et al. (1998), Lynch et al. concluded that a NOAEL from a 90-day drinking water study in 
  28  Contains Nonbinding Recommendations 
 
955  rats using 0.5 to 500 ppm APT was 50 ppm based on lower mean body weight and reduced food 
956  consumption at the highest dose (Lynch et al, 1999). This finding is consistent with the earlier 
957  reports from Schroeder et al. (1970). Thus, the PDE for oral exposure was determined on the 
958  basis of the lowest NOAEL, i.e., 50 ppm (equivalent to 6.0 mg Sb/kg/day). 
959  Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is 
960  calculated as below: 
961   
962  PDE = 6000 g/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 1200 g/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 g/kg/d x 3/7 x 50 kg / (5 x 10 x 5 x 1 x 1) = 94 g/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 g/day 
996     
  29  Contains Nonbinding Recommendations 
 
997  REFERENCES 
998  ATSDR. Toxicological profile for antimony and compounds. Agency for Toxic Substances and 
999  Disease Registry, Public Health Service, US Department of Health and Human Services, Atlanta, 
1000  GA. 1992. 
1001  Lynch BS, Capen CC, Nestmann ER, Veenstra G, Deyo JA. Review of subchronic/chronic 
1002  toxicity of antimony potassium tartrate. Reg Toxicol Pharmacol 1999;30(1):9-17. 
1003  Newton PE, Bolte HF, Daly IW, Pillsbury BD, Terrill JB, Drew RT et al. Subchronic and 
1004  chronic inhalation toxicity of antimony trioxide in the rat. Fundam Appl Toxicol 1994;22:561-
1005  76. 
1006  NTP. Technical report on toxicity studies of antimony potassium tartrate in F344/N rats and 
1007  B6C3F mice (drinking water and intraperitoneal injection studies). National Toxicology Program, 
1 
1008  Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, 
1009  NC. 1992; NTP Toxicity Report Series No. 11. 
1010  Poon R, Chu I, Lecavalier P, Valli VE, Foster W, Gupta S et al. Effects of antimony on rats 
1011  following 90-day exposure via drinking water. Food Chem Toxicol 1998;36:20-35. 
1012  Schroeder HA, Mitchner M, Nasor AP, Balassa JJ, Kanisawa M. Zirconium, niobium, antimony 
1013  and fluorine in mice: effects on growth, survival and tissue levels. J Nutr 1968;95:95-101. 
1014  Schroeder HA, Mitchner M, Nasor AP. Zirconium, niobium, antimony, vanadium and lead in 
1015  rats: life term studies. J. Nutr 1970;100(1):59-68. 
1016  WHO. Antimony in drinking-water. Background document for development of WHO guidelines 
1017  for drinking-water quality. World Health Organization, Geneva. 2003. 
1018  WHO/SDE/WSH/03.04/74 
1019     
  30  Contains Nonbinding Recommendations 
 
1020  ARSENIC 
1021   
1022  Summary of PDE for Arsenic 
Arsenic (As) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  15  15  1.9 
1023   
1024  Introduction 
1025  Arsenic (As) is ubiquitous in the environment and present in food, soil, drinking water and in air. 
1026  Inorganic arsenic occurs in trivalent (e.g., arsenic trioxide, sodium arsenite) or pentavalent (e.g., 
1027  sodium arsenate, arsenic pentoxide, arsenic acid) forms. Arsenic has no known useful biological 
1028  function in human or mammalian organisms. This assessment focuses on inorganic arsenic 
1029  because this is most relevant for drug products. 
1030   
1031  Safety Limiting Toxicity 
1032  Inorganic arsenic has shown to be genotoxic, but not mutagenic and has been acknowledged as a 
1033  human carcinogen (Group 1; IARC, 2012). 
1034  Due to its ubiquitous nature and toxicity profile, there have been many risk assessments 
1035  conducted of arsenic and arsenic compounds, which utilize non-threshold, linear dose response 
1036  approaches (Meharg and Raab, 2010). 
1037  For the most part the effects of arsenic in humans have not been reproduced in animals, so the 
1038  risk assessments have to rely heavily upon epidemiology data in populations with high exposure 
1039  concentrations (Schuhmacher-Wolz et al., 2009). In humans, both cancer and non-cancer effects 
1040  have been linked to arsenic exposure. Oral exposure has been linked to cancers of the skin, liver, 
1041  lung, kidney, and bladder. Following inhalation exposure there is evidence for an increased risk 
1042  of lung cancer (ATSDR, 2007; IARC, 2012; EU EFSA, 2009; WHO, 2011; US EPA, 2010). 
1043  The skin (dyspigmentation, palmoplantar keratosis) and gastrointestinal tract (e.g., nausea) appear 
1044  to be the most sensitive targets for non-cancer adverse effects after oral ingestion while vascular 
1045  disease, reproductive effects and neurological effects are also reported as non-cancer endpoints 
1046  (IARC, 2012; Schuhmacher-Wolz et al., 2009; US EPA, 2007). Oral exposure studies suggest 
1047  that skin lesions may appear at levels above 0.02 mg As/kg/day; no effects were generally seen 
1048  at levels from 0.0004 to 0.01 mg As/kg/day (ATSDR, 2007). There are insufficient 
1049  epidemiological data to set a LOEL or NOEL for other endpoints. The regions of hyperkeratosis 
1050  may evolve into skin cancers (ATSDR, 2007) and can possibly be considered predictive of skin 
1051  and internal cancers and the non-cancer long-term adverse health effects (Chen et al, 2005; Hsu 
1052  et al., 2013; Ahsan and Steinmaus, 2013). 
1053  Studies of large populations (~40,000) exposed to arsenic concentrations in well water at 1000 
1054  g/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 (<100200 
1057  g/L) (Chu and Crawford-Brown, 2006, 2007; Mink et al., 2008). This is consistent with the 
1058  work of Schuhmacher-Wolz et al., (2009). 
  31  Contains Nonbinding Recommendations 
 
1059  An inhalation unit risk for cancer of 0.0043 per g/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 g/m3. This URF translates to an 
1064  air concentration of 0.067 g/m3 at a risk of 1 in 100,000 excess lung cancer mortality 
1065  (Erraguntla et al., 2012). 
1066   
1067  PDE  Oral Exposure 
1068   
1069  The oral PDE is based on the chronic effects of arsenic to skin and sets the limit at 15 g/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 g/day 
1074  No modifying factors were applied because they are incorporated into the derivation of the MRL. 
1075   
1076  PDE  Parenteral Exposure 
1077  The oral bioavailability of arsenic is ~95%. The most direct evidence is from a study that 
1078  evaluated the 6-day elimination of arsenic in healthy humans who were given water from a high-
1079  arsenic sampling site (arsenic species not specified) and that reported approximately 95% 
1080  absorption (Zheng et al., 2002). Therefore, the PDE is identical to the oral PDE. 
1081  PDE = 15 g/day 
1082   
1083  PDE  Inhalation Exposure 
1084  Increased risk of lung cancer and other respiratory disorders have been reported following 
1085  inhalation exposure to workers in the occupational setting. The rationale for using a cancer 
1086  endpoint for inhalation to set the PDE is the relative lack of information on linear-dose 
1087  extrapolation, as compared to the oral route. No modifying factors are needed as the URF were 
1088  determined for the protection of the general public. Based on the assessment conducted by 
1089  Erraguntla et al. (2012), based on the risk of 1:100.000, the inhalation PDE is: 
1090   
1091  PDE = 0.067 g/m3 / 1000 L/m3 x 28800 L/d = 1.9 g/day 
1092   
1093  No modifying factors were applied because the PDE is based on a URF derived from the 
1094  multiplicate relative risk model described by Erraguntla et al. (2012). 
1095   
1096  REFERENCES 
1097  Ahsan H, Steinmaus C. Invited commentary: use of arsenical skin lesions to predict risk of 
1098  internal cancer-implications for prevention and future research. Am J Epidemiol 2013;177:213-6. 
1099  ATSDR. Toxicological profile for arsenic. Agency for Toxic Substances and Disease Registry, 
1100  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2007. 
  32  Contains Nonbinding Recommendations 
 
1101  Chen CJ, Hsu LI, Wang CH, Shih WL, Hsu YH, Tseng MP et al. Biomarkers of exposure, effect, 
1102  and susceptibility of arsenic-induced health hazards in Taiwan. Toxicol Appl Pharmacol 
1103  2005;206:198-206. 
1104  Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a 
1105  metaanalysis for dose-response assessment. Int J Environ Res Public Health 2006;3:316-22. 
1106  Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a 
1107  metaanalysis for dose-response assessment. Int J Environ Res Public Health 2007;4:340-1. 
1108  Erraguntla NK, Sielken RL Jr, Valdez-Flores C, Grant RL. An updated inhalation unit risk factor 
1109  for arsenic and inorganic arsenic compounds based on a combined analysis of epidemiology 
1110  studies. Regul Toxicol Pharmacol 2012;64:329-41. 
1111  EU EFSA. Scientific opinion on arsenic in food. European Food Safety Authority. EFSA Journal 
1112  2009;7(10):1351. 
1113  Hsu LI, Chen GS, Lee CH, Yang TY, Chen YH, Wang YH et al. Use of arsenic-induced 
1114  palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal malignancy. 
1115  Am J Epidemiol 2013;173:202-12. 
1116  IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on the 
1117  Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 
1118  World Health Organization, Lyon. 2012;100C. 
1119  Meharg AA, Raab A. Getting to the bottom of arsenic standards and guidelines. Environ Sci 
1120  Technol 2010;44:4395-9. 
1121  Mink PJ, Alexander DD, Barraj LM, Kelsh MA, Tsuji JS. Low-level arsenic exposure in 
1122  drinking water and bladder cancer: a review and meta-analysis. Regul Toxicol Pharmacol 
1123  2008;58:299-310. 
1124  Schuhmacher-Wolz U, Dieter HH, Klein D, Schneider K. Oral exposure to inorganic arsenic: 
1125  and evaluation of its carcinogenic and non-carcinogenic effects. Crit Rev Toxicol 2009;39:271-
1126  98. 
1127  US EPA. Arsenic, inorganic (CASRN 7440-38-2). Integrated Risk Information System (IRIS). 
1128  1998. US EPA. Inorganic arsenic. TEACH Chemical Summary. 2007. 
1129  US EPA. Toxicological review of inorganic arsenic (CAS No. 7440-38-2). In support of 
1130  summary information on the Integrated Risk Information System (IRIS). 2010. 
1131  WHO. Arsenic in drinking-water. Background document of development of WHO Guidelines 
1132  for Drinking-water quality. World Health Organization, Geneva. 2011. 
1133  WHO/SDE/WSH/03.04/75/Rev/1. 
1134  Zheng Y, Wu J, Ng JC, Wang G, Lian W. The absorption and excretion of fluoride and arsenic 
1135  in humans. Toxicol Lett 2002;133:77-82. 
1136     
  33  Contains Nonbinding Recommendations 
 
1137  BARIUM 
1138   
1139  Summary of PDE for Barium 
Barium (Ba) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  1460  730  343 
1140   
1141  Introduction 
1142  Barium (Ba) is a dense, silver-white, soft alkaline earth metal that oxidizes readily in moist air and 
1143  reacts with water. The Ba(2+) ion and the water soluble compounds of barium (chloride, nitrate, 
1144  hydroxide) are toxic. The insoluble compounds of barium, such as barium sulfate, do not 
1145  generate free Ba(2+) ions in the gastrointestinal tract and therefore are generally nontoxic to 
1146  humans. Barium is nutritionally not essential and no metabolic function is known. Barium sulfate 
1147  has multiple uses e.g., as a radiocontrast medium, a colorant in paint and in the manufacture of 
1148  glass and other products (ATSDR, 2007). 
1149   
1150  Safety Limiting Toxicity 
1151  In animals and humans, the kidney appears to be the most sensitive target of toxicity resulting 
1152  from repeated ingestion of soluble barium salts. Chronic rodent studies support the evidence for 
1153  an association between barium exposure and renal toxicity (NTP, 1994). The lesions were 
1154  characterized by tubule dilatation, renal tubule atrophy, tubule cell regeneration, hyaline cast 
1155  formation, multifocal interstitial fibrosis, and the presence of crystals, primarily in the lumen of 
1156  the renal tubules. These changes were characterized as morphologically distinct from the 
1157  spontaneous degenerative renal lesions commonly observed in aging mice. Effects on blood 
1158  pressure may be the most sensitive endpoint observed in humans after environmental exposure 
1159  (WHO, 2004). Repeated exposure to barium oxide via inhalation may cause bronchitis, including 
1160  cough, phlegm, and/or shortness of breath (CICAD, 2001). 
1161   
1162  PDE  Oral Exposure 
1163  In an evaluation conducted in two towns in Illinois, no significant differences in blood pressure or 
1164  in the prevalence of cardiovascular or kidney disease was found between populations drinking 
1165  water containing a mean barium concentration of 7.3 mg/L or 0.1 mg/L (WHO, 2004). Using the 
1166  NOAEL of 
1167  7.3 mg/L obtained from this study, and using 2 L/day as an estimation of water intake, the oral 
1168  PDE can be calculated as: 
1169   
1170  PDE = 14.6 mg/d / (1 x 10 x 1 x 1 x 1) = 1.46 mg/d = 1460 g/day 
1171   
1172  PDE  Parenteral Exposure 
1173  No relevant data on parenteral exposure to barium compounds were found. The bioavailability of 
1174  barium is estimated to be 20-60% in adults and infants, respectively (ATSDR, 2007). Thus, the 
1175  parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 (as described 
1176  in section 3.1). 
1177  PDE = 1460 g/d / 2 = 730 g/day 
  34  Contains Nonbinding Recommendations 
 
1178   
1179  PDE  Inhalation Exposure 
1180  No relevant data on inhalation exposure to barium compounds were found. United States 
1181  Department of Labor (US DoL, 2013) has a reported Time Weighted Average (TWA) of 0.5 
1182  mg/m3 based on soluble barium salts. 
1183  Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation 
1184  PDE is calculated as: 
1185   
1186  For continuous dosing  =  500 g/ m3 x 8 hr/d x 5 d/wk  =  119 g/ m3 =  0.119 g/L 
1187        24 hr/d x 7 d/wk      1000 L/m3 
1188   
1189  Daily dose =  0.119 g/L x 28800 L =  68.6 g/kg 
1190              50 kg 
1191   
1192  PDE = 68.6 g/kg x 50 kg / (1 x 10 x 1 x 1 x 1) =   343 g/day 
1193   
1194  REFERENCES 
1195  ATSDR. Toxicological profile for barium and barium compounds. Agency for Toxic Substances 
1196  and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, 
1197  Atlanta, GA. 2007. 
1198  CICAD. Barium and barium compounds. Concise International Chemical Assessment Document 
1199  33. World Health Organization, Geneva. 2001. 
1200  NTP. Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate 
1201  (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). National 
1202  Toxicology Program, Public Health Service, U.S. Department of Health and Human Services, 
1203  Research Triangle Park, NC. 1994;NTP TR 432. 
1204  US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
1205  Labor. 2013. 
1206  WHO. Barium in drinking-water: Background document for development of WHO guidelines 
1207  for drinking-water quality. World Health Organization, Geneva. 2004. 
1208  WHO/SDE/WSH/03.04/76. 
1209     
  35  Contains Nonbinding Recommendations 
 
1210  CADMIUM 
1211   
1212  Summary of PDE for Cadmium 
Cadmium (Cd) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  5.0  1.7  3.4 
1213   
1214  Introduction 
1215  Cadmium (Cd) is a transition metal whose most abundant naturally-occurring isotope is non-
1216  radioactive. It is found in nature in mineral forms and is obtained for commercial uses principally 
1217  from cadmium ore (ATSDR, 2012). Cadmium exists as a salt form in the +2 oxidation state only. 
1218  Some cadmium salts such as cadmium chloride, cadmium sulfate and cadmium nitrate are water 
1219  soluble; other insoluble salts can become more soluble by interaction with acids, light or oxygen. 
1220  Cadmium, cadmium oxide, cadmium salts on borosilicate carrier are used as catalysts in organic 
1221  synthesis. Silver cadmium alloy is used in the selective hydrogenation of carbonyl compounds. 
1222   
1223  Safety Limiting Toxicity 
1224  Cadmium has shown to be genotoxic, but not mutagenic and has been acknowledged as a human 
1225  carcinogen (Group 1; IARC, 2012). Cadmium and cadmium compounds cause cancer of the lung. 
1226  Also, positive associations have been observed between exposure to cadmium and cadmium 
1227  compounds and cancer of the kidney and of the prostate. 
1228  A sensitive endpoint for oral exposure to cadmium and cadmium salts is renal toxicity (Buchet et 
1229  al. 1990). Skeletal and renal effects are observed at similar exposure levels and are a sensitive 
1230  marker of cadmium exposure (ATSDR, 2012). 
1231  Evidence from numerous epidemiologic studies assessing inhalation exposures to cadmium via 
1232  both occupational and environmental routes has demonstrated an increased risk of developing 
1233  cancer (primarily lung) that correlates with inhalation exposure to cadmium (IARC, 2012; NTP, 
1234  1995). ATSDR (2012) concluded that lung carcinogenesis due to occupational exposure was 
1235  equivocal. Cadmium was clearly positive for lung tumors in rats; non-significant, non-dose 
1236  dependent in mice; and not observed in hamsters. An inhalation unit risk estimate of 
1237  0.0018/g/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 g/m3 for cadmium (Cadmium OSHA, 2004). 
1240   
1241  PDE  Oral Exposure 
1242  A sensitive endpoint for oral exposure to cadmium and cadmium salts is renal toxicity (Buchet et 
1243  al, 1990). Skeletal and renal effects are observed at similar exposure levels and are a sensitive 
1244  marker of cadmium exposure (ATSDR, 2012). A number of oral exposure studies of cadmium in 
1245  rats and mice showed no evidence of carcinogenicity. Therefore, the renal toxicity endpoint was 
1246  used to establish the oral PDE for cadmium, following the recommendations of ATSDR, an 
1247  MRL of 0.1 g/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 g/kg/d x 50 kg = 5.0 g/day 
  36  Contains Nonbinding Recommendations 
 
1251   
1252  No modifying factors were applied because they are incorporated into the derivation of the MRL. 
1253   
1254  PDE  Parenteral Exposure 
1255  A 12-week study in rats given daily subcutaneous injections of 0.6 mg/kg Cd, 5 days per week 
1256  showed renal damage at week 7 and later (Prozialeck et al, 2009). A single dose level was used 
1257  in this study. The LOAEL of this study is 0.6 mg/kg based on decreased body weight, increased 
1258  urine volume and urinary biomarkers seen at this dose level. This study was used to set the 
1259  parenteral PDE. In a separate single dose study where rats were administered a 0, 1, 2, 4, 8, 16 or 
1260  32 mol/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 g/day 
1270   
1271  A factor of five was chosen for F4 because cadmium is carcinogenic by the inhalation route and 
1272  granulomas were observed by the subcutaneous route. These findings are of uncertain relevance. 
1273  A factor of ten was chosen for F5 because a LOAEL was used to set the PDE. 
1274   
1275  PDE  Inhalation Exposure 
1276  The United States Department of Labor Occupational Safety and Health Administration has 
1277  developed a Permitted Exposure Level of 5 g/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 g/ m3 x 8 hr/d x 5 d/wk  =      1.19 g/m3 =      0.00119 g/L 
1282        24 hr/d x 7 d/wk     1000 L/m3 
1283   
1284  Daily dose =  0.00119 g/L x 28800 L = 0.685 g/kg 
1285              50 kg 
1286   
1287  PDE = 0.685 g/kg x 50 kg / (1 x 10 x 1 x 1 x 1) =   3.43 g/day 
1288   
1289  A modifying factor for F4 of 1 was chosen based on the potential for toxicity to be mitigated by 
1290  the possible species specificity of tumorigenesis, uncertain human occupational tumorigenesis, 
1291  ambient exposure levels not expected to be a health hazard, and workplace exposure levels 
1292  expected to be safe. A larger factor F4 was not considered necessary as the PDE is based on a 
1293  PEL. 
1294     
  37  Contains Nonbinding Recommendations 
 
1295  REFERENCES 
1296  ATSDR. Toxicological profile of cadmium. Agency for Toxic Substances and Disease Registry, 
1297  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. 
1298  Buchet JP, Lauwerys R, Roels H, Bernard A, Bruaux P, Claeys F et al. Renal effects of cadmium 
1299  body burden of the general population. Lancet 1990;336:699-702. 
1300  Cadmium: OSHA 3136-06R, 2004. (available at 
1301  https://www.osha.gov/Publications/osha3136.pdf; accessed October 10, 2017) 
1302  IARC. Arsenic, metals, fibers, and dusts: a review of human carcinogens. Monographs on the 
1303  Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 
1304  World Health Organization, Lyon. 2012;100C. 
1305  NTP. Technical report on toxicity studies of cadmium oxide (CAS No. 1306-19-0) 
1306  administered by inhalation to F344/N Rats and B6C3F mice. National Toxicology 
1 
1307  Program, Public Health Service, U.S. Department of Health and Human Services. 1995. 
1308  Prozialeck WC, Edwards JR, Vaidya VS, Bonventre JV. Preclinical evaluation of novel urinary 
1309  biomarkers of cadmium nephrotoxicity. Toxicol Appl Pharmacol 2009;238:301-305. 
1310  US EPA. Cadmium. Integrated Risk Information System (IRIS). 1992. 
1311  Waalkes MP, Anver M, Diwan BA. Carcinogenic effects of cadmium in the Noble (NBL/Cr) rat: 
1312  induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions 
1313  of the dorsolateral prostate. Toxicol Sci 1999;52:154-161. 
1314  WHO. Cadmium in drinking-water. Background document for development of WHO Guidelines 
1315  for drinking-water quality. World Health Organization. 2011;WHO/SDE/WSH/03.04/80/Rev/1. 
1316     
  38  Contains Nonbinding Recommendations 
 
1317  CHROMIUM 
1318   
1319  Summary of PDE for Chromium 
Chromium (Cr) 
  Oral  Parenteral  Inhalation 
PDE (g/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 oxid4a nt, chromate, CrO 2-,2  a7 nd dichromate, Cr 
1325  O 2-, being the best known oxyanions. Cr(3+), the most abundant environmental form, is an 
1326  essential element that plays a role in glucose metabolism. Chromium deficiency causes changes 
1327  in the metabolism of glucose and lipids and may be associated with maturity-onset diabetes, 
1328  cardiovascular diseases, and nervous system disorders (Anderson, 1993, 1995). Sources of 
1329  chromium in pharmaceuticals may include colorants, leaching from equipment or container 
1330  closure systems, and catalysts. Except when it is used as a catalyst, intake of chromium from 
1331  pharmaceuticals will be in the form of metallic chromium (Cr(0)) or Cr(3+) rather than the more 
1332  toxic Cr(6+); therefore, for drug products, this safety assessment is based on the known toxicity 
1333  of Cr(3+) and Cr(6+) is excluded from this assessment. If Cr(6+) is used as a catalyst, then the 
1334  assessment should incorporate this form. Chromium present as a colorant (e.g., chromium oxide 
1335  green, chromium hydroxide green) is intentionally added and thus beyond the scope of this 
1336  guidance. 
1337   
1338  Safety Limiting Toxicity 
1339  Rats fed diets containing up to 5% Cr O (equivalent to 1468 mg Cr/kg/day) for a lifetime 
2 3 
1340  showed no adverse effects. In a more recent dietary rat study (Anderson et al, 1997), no adverse 
1341  effects were detected at 15 mg Cr(3+)/kg/day. No specific target organ toxicities have been 
1342  identified for the oral intake of chromium. Generally oral intake of 1.5 mg/kg/day Cr(3+) (US 
1343  EPA, 1998) is not expected to be associated with adverse health. 
1344  The data was reviewed to identify the safety limiting toxicities based on routes of administration. 
1345   
1346  PDE  Oral Exposure 
1347  The 2-year NTP studies (2010) on the carcinogenicity of Cr(3+) picolinate administered in feed 
1348  to rats and mice at 2000, 10000 and 50000 ppm provided the most relevant safety information 
1349  for chromium as present in drug products. The NOAEL was the low dose of 90 mg/kg Cr(3+) 
1350  picolinate (11.9  weight %; 10.7 mg/kg/day Cr(3+)) in rats based on increase in the incidence of 
1351  preputial gland adenoma in male rats at 460 mg/kg. This finding was not dose-dependent and was 
1352  considered an equivocal finding by the study authors. This finding was not observed male mice 
1353  or in the female counterpart in either species (clitoral gland). Taking into account the modifying 
1354  factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as: 
1355   
1356  PDE = 10.7 mg/kg/d x 50 kg / (5 x 10 x 1 x 1 x 1) = 10.7 mg/day 
1357   
  39  Contains Nonbinding Recommendations 
 
1358  PDE  Parenteral Exposure 
1359  Recommendation for the nutritional intravenous administration of Cr(3+) vary per age group 
1360  between 0.05 g/kg/day in preterm infants and 15 g/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 g/d / 10 = 1070 g/day 
1370   
1371  PDE  Inhalation Exposure 
1372  The study by Derelenko et al. (1999) used inhalation of Cr(3+) sulfate particles during 13 weeks 
1373  (6h/day and 5 days per week), and the predominant observed effects were chronic inflammation 
1374  of the airways (mononuclear infiltrate, particular material) and local thickening of alveolar walls. 
1375  The effect was observed at all doses. The LOAEL is 17 mg/m3 (3 mg Cr(3+)/m3). A lack of 
1376  systemic toxicity was noted in a 13-week inhalation study in rats administered soluble or 
1377  insoluble Cr(3+). Based on these data, the inhalation MRL of 0.1g/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 g/day 
1381   
1382  No modifying factors were applied because they are incorporated into the derivation of the MRL. 
1383   
1384  REFERENCES 
1385  Anderson RA. Recent advances in the clinical and biochemical effects of chromium deficiency. 
1386  Prog Clin Biol Res 1993;380:221-34. 
1387  Anderson RA. Chromium and parenteral nutrition. Nutr 1995;11(1 suppl.):83-6. 
1388  ATSDR. Toxicological profile of chromium. Agency for Toxic Substances and Disease Registry, 
1389  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. 
1390  Derelanko MJ, Rinehart WE, Hilaski RJ, Thompson RB, Loser 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, Kloppel H, Oldiges H. Carcinogenicity of sodium dichromate and 
1394  chromium (VI/III) oxide aerosols inhaled by male Wistar rats. Toxicology. 1986;42(2-3):219-32. 
1395  Moukarzel A. Chromium in parenteral nutrition: too little or too much. Gastroenterology 
1396  2009;137:S18- S28. 
1397  NTP. Technical report on the toxicology and carcinogenesis studies of chromium picolinate 
1398  monohydrate (CAS NO. 27882-76-4) in F344/N rats and B6C3F1 mice (feed studies). National 
  40  Contains Nonbinding Recommendations 
 
1399  Toxicology Program, Public Health Service, U.S. Department of Health and Human Services. 
1400  2010;NTP TR 556. 
1401  US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
1402  Labor. 2013. 
1403  US EPA. Chromium (III), insoluble salts. Integrated Risk Information System (IRIS). 1998.   
  41  Contains Nonbinding Recommendations 
 
1404  COBALT 
1405   
1406  Summary of PDE for Cobalt 
Cobalt (Co) 
  Oral  Parenteral  Inhalation 
PDE (g/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 g 
1413  Co/day in the diet (ATSDR, 2004). The Recommended Dietary Allowance of Vitamin B12 
1414  ranges from 0.7 to 2.4 g/day (NAS, 2010), which corresponds to 0.03 to 0.1 g of cobalt. No 
1415  essential biological function of inorganic cobalt in the human body has been identified. Cobalt 
1416  compounds (e.g., cobalt octanoate) are being used as catalysts in selective hydrogenation. 
1417   
1418  Safety Limiting Toxicity 
1419  The International Agency for Research on Cancer (IARC, 2006) concluded that Cobalt sulfate and 
1420  other soluble Co(2+) salts are possible human carcinogens (Group 2B). The data indicate the 
1421  location of tumors is limited to the lung in rats and humans. Cobalt metal was positive for 
1422  mutagenicity in vitro but negative for clastogenicity in vivo. The NTP concluded that there was 
1423  clear evidence of carcinogenicity in male and female mice and rats (NTP, 2013). Human studies 
1424  for carcinogenicity by inhalation are inconclusive and not classified for carcinogenicity (US 
1425  EPA, 2000). Polycythemia is considered to be the most sensitive finding after repeated oral 
1426  exposure to humans (ATSDR, 2004). Inhalation exposure of humans to cobalt has been 
1427  associated with a severe and progressive respiratory disease known as hard-metal 
1428  pneumoconiosis, as well as asthma and contact dermatitis (ATSDR, 2004; IARC, 2006). 
1429   
1430  PDE  Oral Exposure 
1431  The oral PDE is based on the available human data. Polycythemia was a sensitive endpoint in 
1432  humans after repeated oral exposure to 150 mg of cobalt chloride for 22 days (~1 mg Co/kg/day; 
1433  WHO, 2006; ATSDR, 2004). Polycythemia or other effects were not observed in a study of 10 
1434  human volunteers (5 men and 5 women) ingesting 1 mg/Co per day as CoCl for 88-90 days 
2 
1435  (Tvermoes et al, 2014). The oral PDE was determined on the basis of the NOAEL of 1 mg/day. 
1436  Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is 
1437  calculated as below: 
1438   
1439  PDE = 1 mg/d / (1 x 10 x 2 x 1 x 1) = 0.05 mg/d = 50 g/day 
1440   
1441  A factor of 2 was chosen for F3 because a short-term human study was used to set the PDE. 
1442   
1443  PDE  Parenteral Exposure 
1444  No relevant data on parenteral exposure to cobalt compounds were found. The oral 
1445  bioavailability of cobalt and inorganic cobalt compounds ranges from 18-97% (ATSDR, 2004). 
  42  Contains Nonbinding Recommendations 
 
1446  To account for the low oral bioavailability, the parenteral PDE was calculated by dividing the 
1447  oral PDE by a modifying factor of 10 (as described in section 3.1). The PDE for cobalt for 
1448  parenteral exposure is: 
1449   
1450  PDE = 50 g/d / 10 = 5.0 g/day 
1451   
1452  PDE  Inhalation Exposure 
1453  Cobalt sulfate and other soluble Co(2+) salts are possible human carcinogens (Group 2B) that can 
1454  induce lung tumors. 
1455  Pneumoconiosis, asthma and contact dermatitis were the principal non-carcinogenic effects in 
1456  humans after chronic inhalation. The MRL approach was considered acceptable for cobalt as the 
1457  data are considered more reliable and the lack of human data for carcinogenicity cobalt sulfate. 
1458  The best estimate of human cancer risk is approximately the same as the PDE derived using the 
1459  MRL (WHO, 2006). For the calculation of the inhalation PDE, the chronic inhalation MRL of 
1460  0.1 g/ m3 was used (ATSDR, 2004). 
1461   
1462  PDE = 0.0001 mg/ m3 /1000 m3/L x 28800 L/d = 2.9 g/day 
1463   
1464  No modifying factors were applied because they are incorporated into the derivation of the MRL. 
1465   
1466  REFERENCES 
1467  ATSDR. Toxicological profile for cobalt. Agency for Toxic Substances and Disease Registry, 
1468  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2004. 
1469  IARC. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and 
1470  vanadium pentoxide. International Agency for Research on Cancer, World Health Organization, 
1471  Lyon. 2003;86, updated in 2006. 
1472  NAS.IOM. Food and Nutrition Board. Dietary Reference Intakes: RDA and AI for vitamins and 
1473  elements. Institute of Medicine National Academies. Summary Tables, 2010. (available online at 
1474  http://fnic.nal.usda.gov/dietary-guidance/dietary-reference-intakes/dri-tables; accessed May 27, 
1475  2014) 
1476  NTP. Technical report on the toxicology studies of cobalt metal (CAS No. 7440-48-4) in F344/N 
1477  rats and B6C3F1/N mice and toxicology and carcinogenesis studies of cobalt metal in 
1478  F344/NTac rats and B6C3F1/N mice (inhalation studies). National Toxicology Program, Public 
1479  Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC. 
1480  2013;NTP TR 581. 
1481  Tvermoes BE, Unice KM, Paustenbach DJ, Finley BL, Otani JM, Galbraith DA. Effects and 
1482  blood concentrations of cobalt after ingestion of 1 mg/day by human volunteers for 90 d. Am J 
1483  Clin Nutr 2014;99:632-646. 
1484  US EPA. Cobalt compounds: technology transfer network air toxics web site: Hazard summary. 
1485  2000 (http://www.epa.gov/ttn/atw/hlthef/cobalt.html; accessed April 23, 2014). 
  43  Contains Nonbinding Recommendations 
 
1486  WHO. Cobalt and inorganic cobalt compounds. Concise International Chemical Assessment 
1487  Document. Inter-Organization Programme for the Sound Management of Chemicals (IOMC). 
1488  World Health Organization. 2006;69.   
  44  Contains Nonbinding Recommendations 
 
1489  COPPER 
1490  Summary of PDE for Copper 
Copper (Cu) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  3400  340  34 
1491   
1492  Introduction 
1493  Copper (Cu) is a Group 11 element of the first transition series and has two main oxidation states, 
1494  Cu(1+) and Cu(2+). It is an essential trace element in both animals and humans. Copper plays a 
1495  vital role in a number of critical enzyme systems and is closely linked with normal 
1496  hematopoiesis and cellular metabolism. Copper compounds (e.g., copper chromite) are being 
1497  used as catalysts in hydrogenolysis and decarboxylation reactions. 
1498   
1499  Safety Limiting Toxicity 
1500  A general review of relevant safety data for animals and humans indicates that copper can 
1501  produce adverse effects to the gastrointestinal tract, liver, and kidney upon ingestion of toxic 
1502  doses (Araya et al, 2003). 
1503   
1504  PDE  Oral Exposure 
1505  Studies on cupric sulfate and copper 8-quinolinolate have been conducted in mice, rats, and dogs 
1506  (IPCS, 1998). Rats were determined to be the most sensitive of these species to effects on liver 
1507  and kidney. In a 13-week study in which rats were fed 500 to 8000 ppm cupric sulfate 
1508  pentahydrate, the NOEL for hyperplasia and hyperkeratosis of the forestomach mucosa was 1000 
1509  ppm. Hepatic and renal toxicity was observed from doses equal to and greater than 2000 ppm. 
1510  The NOEL was 1000 ppm, equivalent to 64 mg CuSO /kg/day (17 mg Cu/kg/day). (Hebert et al, 
4
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 g/day 
1515   
1516  PDE  Parenteral Exposure 
1517  The safety review for copper was unable to identify any significant assessments upon which to 
1518  calculate a PDE for parenteral routes of exposure. The human gastrointestinal system can absorb 
1519  30-40% of ingested copper from the typical diets consumed in industrialized countries (Wapnir, 
1520  1998). On the basis of limited oral bioavailability of 30-40% for copper and inorganic copper 
1521  salts, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as 
1522  described in section 3.1). The recommended PDE for copper for parenteral exposure is: 
1523   
1524  PDE = 3400 g/d / 10 = 340 g/day 
1525   
1526  PDE  Inhalation Exposure 
1527  The available data on the toxicity of inhaled copper were considered inadequate for derivation of 
1528  acute- intermediate-,  or  chronic-duration inhalation  MRLs  (ATSDR,  2004).  The inhalation 
  45  Contains Nonbinding Recommendations 
 
1529  PDE was calculated by dividing the oral PDE by a modifying factor of 100 (as described in 
1530  section 3.1). 
1531   
1532  PDE = 3400 g/day / 100 = 34 g/day 
1533   
1534  REFERENCES 
1535  Araya M, Olivares M, Pizarro F, Gonzalez 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  Hebert CD, Elwell MR, Travlos GS, Fitz CJ, Bucher JR. Subchronic toxicity of cupric sulfate 
1541  administered in drinking water and feed to rats and mice. Fundam Appl Toxicol 1993;21:461-
1542  475. 
1543  IPCS. Copper. Environmental Health Criteria 200. International Programme on Chemical Safety. 
1544  World Health Organization, Geneva. 1998. 
1545  Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr 1998;67(suppl):1054S-60S 
1546     
  46  Contains Nonbinding Recommendations 
 
1547  GOLD 
1548   
1549  Summary of PDE for Gold 
Gold (Au) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  322  322  3.2 
1550   
1551  Introduction 
1552  Gold (Au) exists in metallic form and in oxidation states of +1 to +5, the monovalent and trivalent 
1553  forms being the most common. Elemental gold is poorly absorbed and consequently is not 
1554  considered biologically active. Gold is being used on a carrier or in complexes like gold chloride 
1555  and L-Au+ (where L is a phosphane, phosphite, or an arsine; Telles, 1998), as catalysts in organic 
1556  synthesis. The only source for gold in drug products comes from the use as catalyst. Au(1+) salts 
1557  are used therapeutically. 
1558   
1559  Safety Limiting Toxicity 
1560  Most knowledge of gold toxicity is based on therapeutic uses of gold. Currently available 
1561  therapies are gold salts of monovalent Au(1+) with a sulfur ligand (Au-S), but metallic gold has 
1562  also been studied. No toxicity was seen in ten patients administered colloidal metallic gold 
1563  (monoatomic gold) at 30 mg/day for one week followed by 60 mg/day the second week or the 
1564  reverse schedule. The patients were continued on the trial for an additional 2 years at 30 mg/day. 
1565  There was no evidence of hematologic, renal, or hepatic cytotoxicity but some improvement in 
1566  clinical symptoms of rheumatoid arthritis and in cytokine parameters were noted (Abraham and 
1567  Himmel, 1997). 
1568  Long term animal and human data are available with gold compounds. Toxicities include renal 
1569  lesions in rats administered gold compounds by injection (Payne and Saunders, 1978) and 
1570  humans (Lee et al, 1965) and gastrointestinal toxicity in dogs (Payne and Arena, 1978). 
1571  However, these studies have been performed with monovalent gold (Au(1+)) or forms of gold 
1572  not present as pharmaceutical impurities and thus are not considered sufficiently relevant to 
1573  derive a PDE for gold in pharmaceutical products. 
1574  There are no relevant toxicology studies in humans or animals by the oral route of a form of gold 
1575  likely to be in a pharmaceutical product to set an oral PDE of gold. Au(3+) is thought to be the 
1576  more toxic form and is used in catalysis, e.g., as gold trichloride. There is only limited data on 
1577  Au(3+) complexes. In one study, the Au(3+) compound [Au(en)Cl ]Cl 
2
1578  (dichloro(ethylenediamine-aurate3+ ion) caused minimal histological changes in the kidney and 
1579  liver of rats, and no renal tubular necrosis, at a dose of 32.2 mg/kg in rats administered the 
1580  compound intraperitoneal for 14 days (Ahmed et al, 2012). 
1581   
1582  PDE  Oral Exposure 
1583  The toxicologically significant endpoint for gold exposures is renal toxicity. The study in rats 
1584  administered Au(3+) by the intraperitoneal route was considered acceptable in setting the oral 
1585  PDE because the renal endpoint of toxicity is a sensitive endpoint of gold toxicity. Taking into 
1586  account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as: 
1587   
  47  Contains Nonbinding Recommendations 
 
1588  PDE = 32.2 mg/kg x 50 kg / (5 x 10 x 10 x 1 x 10) = 322 g/day 
1589   
1590  A factor of ten for F5 was chosen because the LOAEL is used to establish the PDE and the 
1591  toxicological assessment was not complete. 
1592   
1593  PDE  Parenteral Exposure 
1594  In humans, 50 mg intramuscular injections of gold sodium thiomalate resulted in >95% 
1595  bioavailability (Blocka et al, 1986). In rabbits, approximately 70% of the gold sodium thiomalate 
1596  was absorbed after an intramuscular injection of 2mg/kg (Melethil and Schoepp, 1987). Based on 
1597  high bioavailability, and that a study by the intraperitoneal route was used to set the oral PDE, 
1598  the parenteral PDE is equal to the oral PDE. 
1599   
1600  PDE = 322 g/day 
1601   
1602  PDE  Inhalation Exposure 
1603  In the absence of relevant inhalation data, including the potential local tissue toxicity of the 
1604  effects of gold in lungs, the inhalation PDE was calculated by dividing the oral PDE by a 
1605  modifying factor of 100 (as described in section 3.1). 
1606   
1607  PDE = 322 g/d / 100 = 3.22 g/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)Cl ]Cl. PLoS ONE 2012;7(12):1-11. 
2
1614  Blocka KL, Paulus HE, Furst DE. Clinical pharmacokinetics of oral and injectable gold 
1615  compounds. Clin Pharmacokinet 1986;11:133-43. 
1616  Lee JC, Dushkin M, Eyring EJ, Engleman EP, Hopper J Jr. Renal Lesions Associated with Gold 
1617  Therapy: Light and Electron Microscopic Studies. Arthr Rheum 1965;8(5):1-13. 
1618  Melethil S, Schoepp D. Pharmacokinetics of gold sodium thiomalate in rabbits. Pharm Res 
1619  1987;4(4):332-6. 
1620  Payne BJ, Arena E. The subacute and chronic toxicity of SK&F 36914 and SK&F D-39162 in 
1621  dogs. Vet Pathol 1978;15(suppl 5): 9-12. 
1622  Payne BJ, Saunders LZ. Heavy metal nephropathy of rodents. Vet Pathol 1978;15(suppl 5):51-
1623  87. 
1624  Telles JH, Brode S, Chabanas M. Cationic gold (I) complexes: highly efficient catalysts for the 
1625  addition of alcohols to alkynes. Angew Chem Int Ed 1998;37:1415-18   
  48  Contains Nonbinding Recommendations 
 
1626  LEAD 
1627   
1628  Summary of PDE for Lead 
Lead (Pb) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  5.0  5.0  5.0 
1629   
1630  Introduction 
1631  Lead (Pb) occurs in organic and inorganic forms. The generally bivalent lead compounds include 
1632  water- soluble salts such as lead acetate as well as insoluble salts such as lead oxides. Organic 
1633  lead compounds include the gasoline additives tetramethyl- and tetraethyl-lead. Organic lead 
1634  compounds undergo fairly rapid degradation in the atmosphere and form persistent inorganic 
1635  lead compounds in water and soil. Lead has no known biological function in human or 
1636  mammalian organisms (ATSDR, 2007). 
1637  Safety Limiting Toxicity 
1638  In humans and animals, exposure to lead may cause neurological, reproductive, developmental, 
1639  immune, cardiovascular and renal health effects. In general, sensitivity to lead toxicity is greater 
1640  when there is exposure in utero and in children compared to adults. A target blood level of 1-2 
1641  g/dL was set, and using modelling programs (US EPA, 2009) that assumed 100% 
1642  bioavailability and no other exposure, a PDE was obtained. For this reason, the PDEs are the 
1643  same regardless of the route of administration. 
1644   
1645  PDE  Oral Exposure 
1646  Adverse neurobehavioral effects are considered to be the most sensitive and most relevant 
1647  endpoint in humans after oral exposure. Data from epidemiological studies show that blood lead 
1648  levels <5 g/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 g/day translates into a blood level 
1651  of 1-2 g/dL for children age 0-7 years (0-82 months) (US EPA, 2007, 2009). 
1652   
1653  PDE = 5.0 g/day 
1654   
1655  PDE  Parenteral Exposure 
1656  The oral effects of Pb are based on blood levels. Therefore, the parenteral PDE is equal to the oral 
1657  PDE.  
1658   
1659  PDE = 5.0 g/day 
1660   
1661  PDE  Inhalation Exposure 
1662  The oral effects of Pb are based on blood levels. Therefore, the inhalation PDE is equal to the oral 
1663  PDE.  
1664   
  49  Contains Nonbinding Recommendations 
 
1665  PDE = 5.0 g/day 
1666   
1667  REFERENCES 
1668  ATSDR. Toxicological profile for lead. Agency for Toxic Substances and Disease Registry, 
1669  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2007. 
1670  NTP. Monograph on health effects of low-level lead. National Toxicology Program, U.S. 
1671  Department of Health and Human Services. 2012. 
1672  US EPA. Users Guide for the Integrated Exposure Uptake Biokinetic Model for Lead in 
1673  Children (IEUBK) Windows. 2007. 
1674  US EPA. Integrated Exposure Uptake Biokinetic (IEUBK) Model for Lead. 1994, updated 2009. 
1675  (http://www.epa.gov/superfund//health/contaminants/lead/products.htm; Accessed March 25, 
1676  2014)   
  50  Contains Nonbinding Recommendations 
 
1677  LITHIUM 
1678   
1679  Summary of PDE for Lithium 
Lithium (Li) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  560  280  25 
1680   
1681  Introduction 
1682  Lithium (Li) is a common metal that is present in plant and animal tissues. Lithium is being used 
1683  alone or in combination with other metals as catalyst. Lithium compounds (e.g., lithium 
1684  aluminum hydride) are being used as reagents in organic synthesis. Lithium exists commonly as 
1685  a salt in the +1 oxidation state only. 
1686   
1687  Safety Limiting Toxicity 
1688  Lithium is used as a human therapeutic, and extensive human data exists in the administration of 
1689  lithium salts in the treatment of mania, bipolar disorder, and recurrent unipolar depression. 
1690  Treatment with lithium salts requires frequent controls by the treating physician, including 
1691  measurement of lithium concentrations. The therapeutic range for lithium has been established at 
1692  0.6-1 mmol/L in serum, depending upon the formulation administered (Grandjean and Aubry, 
1693  2009). The therapeutic margin is narrow and Li toxicity can occur at therapeutic exposures. 
1694  Lithium treatment in humans is mainly associated with an increased risk of reduced urinary 
1695  concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain (McKnight et al, 
1696  2012). The usual recommended dose is 300- 600 mg three to four times a day (US FDA, 2011). 
1697  The data was reviewed to identify the safety limiting toxicities based on routes of administration. 
1698   
1699  PDE  Oral Exposure 
1700  Human experience with lithium was used as the point of departure for this PDE. When using the 
1701  lowest human single oral dose of 300 mg lithium carbonate (56 mg Li), the oral PDE is 
1702  calculated as follows: 
1703   
1704  PDE = 56 mg/d / (1 x 10 x 1 x 1 x 10) = 0.56 mg/d = 560 g/day 
1705   
1706  A factor of ten was chosen for F5 because a LOAEL (one-third the recommended daily dose) 
1707  was used to set the PDE. 
1708   
1709  PDE  Parenteral Exposure 
1710  There are no adequate data to develop a parenteral PDE. However, based on oral bioavailability 
1711  of 85% (Grandjean and Aubry, 2009), the parenteral PDE was calculated by dividing the oral 
1712  PDE by a modifying factor of 2 (as described in section 3.1). 
1713   
1714  PDE = 560 g/d / 2 = 280 /day 
1715   
1716  PDE  Inhalation Exposure 
1717  Rabbits were exposed to lithium chloride at 0.6 and1.9 mg/m3 for 4-8 weeks, 5 days/week for 6 
1718  hours/d (Johansson et al. 1988). Lungs were studied by light and electron microscopy with focus 
  51  Contains Nonbinding Recommendations 
 
1719  on inflammatory changes. No significant effects were reported, so the highest dose was used to 
1720  set the PDE. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the 
1721  inhalation PDE is calculated as: 
1722   
1723  For continuous dosing = 1.9 mg/m3 x 6 h/d x 5 d/wk =   0.34 mg/m3   = 0.00034 mg/L 
1724  24 h/d x 7d/wk             1000 L/m3 
1725   
1726  Daily dose =  0.00034 mg/L x 1440 L/d =   122.04 g/kg/day 
1727          4 kg 
1728   
1729  PDE = 122.04 g/kg/d x 50 kg / (2.5 x 10 x 10 x 1 x 1) = 25 g/day 
1730   
1731  REFERENCES 
1732  Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based 
1733  approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs 
1734  2009;23(4):331-49. 
1735  Johansson A, Camner P, Curstedt T, Jarstrand C, Robertson B, Urban T. Rabbit lung after 
1736  inhalation of lithium chloride. J Appl Toxicol 1988;8:373-5. 
1737  McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity 
1738  profile: a systematic review and meta-analysis. Lancet 2012;379:721-728. 
1739  US FDA. Lithium carbonate product label, 2011. (available at drugs@fda; accessed May 1, 
1740  2014)   
  52  Contains Nonbinding Recommendations 
 
1741  MERCURY 
1742   
1743  Summary of PDE for Mercury 
Mercury (Hg) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  30  3.0  1.2 
1744   
1745  Introduction 
1746  Mercury (Hg) is widely distributed in the global environment. Mercury exists in three forms: 
1747  elemental mercury, inorganic mercury and organic mercury. The most likely form of residual 
1748  mercury in drug products is the inorganic form. Therefore, this safety assessment is based on the 
1749  relevant toxicological data of elemental or inorganic mercury. This safety assessment and derived 
1750  PDEs do not apply to organic mercury. 
1751   
1752  Safety Limiting Toxicity 
1753  There is no data to indicate that inorganic mercury is carcinogenic in human. There is limited 
1754  evidence in experimental animals for the carcinogenicity of mercuric chloride. The International 
1755  Agency for Research on Cancer (IARC) concluded that inorganic mercury compounds are not 
1756  classifiable as to their carcinogenicity to humans (Group 3; IARC, 1997). 
1757  Inorganic mercury compounds show significantly lower oral bioavailability compared to organic 
1758  mercury and induce different toxicological effects including neurological, corrosive, 
1759  hematopoietic, and renal effects, and cutaneous disease (acrodynia). The safety limiting toxicity 
1760  for inorganic mercury and salts is renal toxicity. Direct absorption to the brain via the olfactory 
1761  pathway has been reported (Shimada et al, 2005). 
1762   
1763  PDE  Oral Exposure 
1764  There were well designed NTP studies in rats and mice of HgCl of up to 2 years duration. The 6-
2 
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 HgCl /kg/5d per week) than the 2-year 
2
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 HgCl . In a Joint Expert Committee for Food Additives 
2
1772  (JECFA) assessment (JECFA, 2011) a BMDL of 0.06 mg Hg/kg/day (adjusted from 5 
10 
1773  days/week dosing) was derived based on adverse renal effects (weight increase) from the 6-
1774  month rat study (NTP, 1993). Using the modifying factors (F1-F5 as discussed in Appendix 1) the 
1775  oral PDE is calculated as: 
1776   
1777  PDE = 0.06 mg/kg/d x 50 kg / (5 x 10 x 2 x 1 x 1) = 0.03 mg/d = 30 g/day 
1778   
1779  F4 was set to 1 as the findings in the 6-month and 2-year studies were not considered significant 
1780  at the lowest dose, and F5 was set to 1 as the BMDL can be considered a NOAEL (Sargent et 
10 
1781  al, 2013). 
1782   
  53  Contains Nonbinding Recommendations 
 
1783  PDE  Parenteral Exposure 
1784  Animal studies indicate that the oral bioavailability of inorganic mercury is in the 10-30% range 
1785  (ATSDR, 1999). Therefore, the parenteral PDE was calculated by dividing the oral PDE by a 
1786  modifying factor of 10 (as described in Section 3.1). 
1787   
1788  PDE = 30 g/d / 10 = 3.0 g/day 
1789   
1790  PDE  Inhalation Exposure 
1791  Neurobehavioral effects are considered to be the most sensitive endpoint following inhalation 
1792  exposure in humans as shown in occupational studies at the range of air TWA levels between 14 
1793  and 20 g/m3 (US EPA, 1995; EU SCOEL, 2007). The presence of neurobehavioral effects at 
1794  low-level mercury exposures (14 g/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 g/m3 x 8 hr/d x 6 d/wk =   4 g/m3 = 0.004 g/L 
1799  24 hr/d x 7 d/wk    1000 L/m3 
1800   
1801  Daily dose =     0.004 g/L x 28800 L = 2.30 g/kg 
1802            50 kg 
1803   
1804  PDE = 2.30 g/kg x 50 kg / (1 x 10 x 1 x 1 x 10) = 1.2 g/day 
1805   
1806  A factor of ten for F5 was chosen because a LOAEL was used to set the PDE and to account for 
1807  the possible direct transfer of mercury to the brain through the olfactory pathway. 
1808   
1809  REFERENCES 
1810  ATSDR. Toxicological profile for mercury. Agency for Toxic Substances and Disease Registry, 
1811  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1999. 
1812  EU SCOEL. Recommendation from the scientific committee on occupational exposure 
1813  limits for elemental mercury and inorganic divalent mercury compounds. European 
1814  Union Scientific Committee on Occupational Exposure Limits. 2007;SCOEL/SUM/84. 
1815  IARC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. 
1816  Monographs on the Evaluation of Carcinogenic Risks to Humans. International Agency for 
1817  Research on Cancer,  World Health Organization, Lyon. 1993;58, updated in 1997. 
1818  JECFA. Safety evaluation of certain contaminants in food. WHO Food Additive Series 63. Joint 
1819  Expert Committee on Food Additives. Rome, 2011. 
1820  Ngim CH, Foo SC, Boey KW, and Jeyaratnam J. Chronic neurobehavioural effects of elemental 
1821  mercury in dentists. Br J Ind Med 1992;49(11):782-90. 
1822  NTP. Technical report on the toxicology and carcinogenesis studies of mercuric chloride (CAS No. 
1823  7487- 94-7) in F344 rats and B6C3F1 mice (gavage studies). National Toxicology Program, 
1824  Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, 
1825  NC. 1993;NTP TR 408. 
  54  Contains Nonbinding Recommendations 
 
1826  Sargent EV, Faria E, Pfister T, Sussman RG. Guidance on the establishment of daily exposure 
1827  limits (ADE) to support risk-based manufacture of pharmaceutical products. Reg Toxicol 
1828  Pharmacol 2013;65:242-250. 
1829  Shimada A, Nagayama Y, Morita T et al. Localization and role of metallothioneins in the 
1830  olfactory pathway after exposure to mercury vapor. Exp Toxicol Pathol 2005;57:117-125. 
1831  US EPA. Mercuric chloride (HgCl ) (CASRN 7487-94-7). Integrated Risk Information System 
2
1832  (IRIS). 1995.   
  55  Contains Nonbinding Recommendations 
 
1833  MOLYBDENUM 
1834   
1835  Summary of PDE for Molybdenum 
Molybdenum (Mo) 
  Oral  Parenteral  Inhalation 
PDE (g/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 th4 e molybdate 
1840  ion, MoO 2- which forms soluble compounds with a variety of cations including K+, NH + and 
4 
1841  Ca2+. Mo exists in soil in various forms at concentration of 0.1-10 mg/kg. MoO and MoS are 
2  2 
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  g/day for infants to adults, respectively (EC Scientific Committee on Food, 2000). 
1847  Molybdenum deficiency is characterized by night blindness, nausea, disorientation, coma, 
1848  tachycardia, and tachypnea and associated with various biochemical abnormalities including high 
1849  plasma methionine. In addition, an almost undetectable serum uric acid concentration has been 
1850  reported in a patient receiving total parenteral nutrition (Abumrad et al, 1981). 
1851   
1852  Safety Limiting Toxicity 
1853  Molybdenum as the trioxide was not mutagenic (NTP, 1997) and a Ruksinstutuut Voor 
1854  Volksgezondheid En Milieu (RIVM) assessment concluded that molybdenum is not genotoxic 
1855  (RIVM, 2001). Carcinogenicity has not been evaluated by IARC or US EPA. Molybdenum by 
1856  the oral route has low toxicity. There is some evidence of carcinogenicity in the mouse when 
1857  molybdenum is administered by the inhalation route. The possible carcinogenic effects were 
1858  considered the endpoint of greatest toxicological relevance for this route of exposure. 
1859   
1860  PDE  Oral Exposure 
1861  A good laboratory practice compliant 90-day toxicology study that investigated the toxicity of 
1862  sodium molybdate dehydrate administered in the diet of rats demonstrated effects at 60 mg 
1863  Mo/kg/day, including effects on body weight, weight gain, food conversion efficiency, some 
1864  organ weights (absolute and relative to body weight) and renal histopathology (slight diffuse 
1865  hyperplasia in the proximal tubules in two females) (Murray et al, 2014). No adverse effects 
1866  were noted after a 60-day recovery period, with the exception of reduced body weights in male 
1867  rats. No adverse effects on reproductive organs, estrus cycles, or sperm parameters were noted. 
1868  The authors conclude that the NOAEL for this study was 17 mg Mo/kg/day. No treatment-related 
1869  toxicity was seen at this dose. Using modifying factors (F1-F5 as discussed in Appendix 1) the 
1870  oral PDE is: 
1871   
1872  PDE = 17 mg/kg x 50 kg / (5 x 10 x 5 x 1 x 1) = 3.4 mg/d = 3400 g/day 
1873   
  56  Contains Nonbinding Recommendations 
 
1874  PDE  Parenteral Exposure 
1875  In Vyskocil and Viau (1999), it was reported that oral bioavailability in humans ranged from 28-
1876  77%. Turnland et al. (2005) report that molybdenum absorption was about 90% in healthy men. 
1877  Therefore, the parenteral PDE is divided by a modifying factor of 2 (as described in section 3.1). 
1878   
1879  PDE= 3400 g/day / 2 = 1700 g/day 
1880   
1881  PDE  Inhalation Exposure 
1882  Inhaled molybdenum trioxide was carcinogenic in male and female mice (NTP, 1997) and the 
1883  weight of evidence suggests that calcium and zinc molybdates may be carcinogenic to 
1884  humans (NAS, 2000). Modeling was conducted using the adenoma/carcinoma incidence data 
1885  (combined) in female mice (3/50, 6/50, 8/49, and 15/49 for the 0, 10, 30 and 100 mg/m3 exposure 
1886  groups, respectively) to determine a linear extrapolation, the unit risk of lung cancer is less than 
1887  2.6105/g/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 g/m3 
1891  2.6 x10-5 /g/m3  
1892   
1893  PDE = 0.38 g/m3 / 1000 L/m3 x 28800 L/d = 10.9 g/day 
1894   
1895  No modifying factors are used to adjust a PDE derived by the unit risk approach. 
1896   
1897  REFERENCES 
1898  Abumrad NN, Schneider AJ, Steel D, Rogers LS. Amino acid intolerance during prolonged total 
1899  parenteral nutrition reversed by molybdate therapy. Am J Clin Nutr 1981;34(11):2551-9. 
1900  EC Scientific Committee on Food. Opinion of the Scientific Committee on Food on the tolerable 
1901  upper intake level of molybdenum. European Commission Committee on Food, 2000 (available 
1902  at ec.europa.eu/food/fs/sc/scf/out80h_en.pdf; accessed March 21, 2014). 
1903  Miller RF, Price NO, Engel RW. Added dietary inorganic sulfate and its effect upon rats fed 
1904  molybdenum. J Nutr 1956;60(4):539-47. 
1905  Murray FJ, Sullivan FM, Tiwary AK, Carey S. 90-Day subchronic toxicity study of sodium 
1906  molybdate dihydrate in rats. Regul Toxicol Pharmacol 2013: 
1907  http://dx.doi.org/10.1016/j.yrtph.2013.09.003 (accessed September 29, 2014). 
1908  NAS. Toxicological risks of selected flame-retardant chemicals: Subcommittee on Flame-
1909  Retardant Chemicals, Committee on Toxicology, Board on Environmental Studies and 
1910  Toxicology, National Academy of Sciences National Research Council. 2000. (available at 
1911  http://www.nap.edu/catalog/9841.html; accessed March 21, 2014). 
1912  NTP. Toxicology and carcinogenesis studies of molybdenum trioxide (CAS No. 1313-27-5) in 
1913  F344 rats and B6C3F1 mice (inhalation studies). National Toxicology Program, Public Health 
1914  Service, U.S. Department of Health and Human Services. 1997. 
  57  Contains Nonbinding Recommendations 
 
1915  RIVM. RIVM Report 711701025: Re-evaluation of human-toxicological maximum permissible 
1916  risk levels. Ruksinstutuut Voor Volksgezondheid En Milieu (National Institute of Public Health 
1917  and the Environment). 2001. 
1918  Turnland JR, Keyes WR, Peiffer GL. Molybdenum absorption, excretion, and retention studied 
1919  with stable isotopes in young men at five intakes of dietary molybdenum. Am J Clin Nutr 
1920  1995;62:790-796. 
1921  Vyskocil A, Viau C. Assessment of molybdenum toxicity in humans. J Appl Toxicol 
1922  1999;19:185-192.   
  58  Contains Nonbinding Recommendations 
 
1923  NICKEL 
1924   
1925  Summary of PDE for Nickel 
Nickel (Ni) 
  Oral  Parenteral  Inhalation 
PDE (g/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  g/day (US EPA, 1996). 
1939   
1940  Safety Limiting Toxicity 
1941  Nickel is genotoxic, but not mutagenic (IARC 2012). There is no indication of carcinogenicity of 
1942  Ni salts after oral administration (Heim et al, 2007). Depending on the type of salt there was an 
1943  increase in tumors in some rodent inhalation studies (ATSDR, 2005; EU EFSA, 2005). The US 
1944  EPA has concluded that there is sufficient evidence of carcinogenicity of nickel refinery dust (US 
1945  EPA, 2012). In contrast to nickel refinery dust, no significant increase in cancer risk was found 
1946  in workers in nickel alloy or stainless steel production (ATSDR, 2005). Combining all forms of 
1947  nickel, IARC (2012) classified nickel as a human carcinogen (Group 1). 
1948  In humans and animals, ingestion of large amounts of nickel may cause stomach pain, depression 
1949  of body weight and adverse effects on blood and kidneys. Humans generally become sensitized 
1950  to nickel after prolonged contact with the skin. Human data show that an oral challenge to a 
1951  single dose of nickel administered in drinking water can induce dermatitis in nickel-sensitized 
1952  individuals (Nielsen et al, 1999). In the derivation of the oral reference dose (US EPA, 1996) for 
1953  soluble salts of nickel, individuals with nickel hypersensitivity were not taken into account. 
1954  Chronic inhalation may produce adverse changes such as inflammation in lung and nasal cavity 
1955  in both humans and animals; bronchitis, emphysema, fibrosis, and impaired lung function have 
1956  been reported in nickel welders and foundry workers (ATSDR, 2005). The inflammatory lung 
1957  lesions which developed in rats administered the soluble NiSO were qualitatively similar, but 
4 
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 (Schaumloffel, 2012). 
1961   
1962  PDE  Oral Exposure 
1963  In a 2-year carcinogenicity study in rats administered nickel sulfate hexahydrate at 10, 30 or 50 
1964  mg/kg/day, no treatment-related tumors were observed. There was a significant exposure-
1965  response in mortality in females during weeks 0-105 at all dose levels, and a dose-dependent 
  59  Contains Nonbinding Recommendations 
 
1966  decrease in body weights in both sexes at week 103 that reach significance in the 30 and 50 
1967  mg/kg/day groups (Heim et al, 2007). Using the LOAEL of 10 mg/kg/day (2.2 mg Ni/kg/d), and 
1968  taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is: 
1969   
1970  PDE = 2.2 mg/kg/d x 50 kg / (5 x 10 x 1 x 1 x 10) = 0.22 mg/d = 220 g/day  
1971  A factor of 10 was chosen for F5 because a LOAEL was used to set the PDE. 
1972  PDE  Parenteral Exposure 
1973  A human study using a stable nickel isotope estimated that 29-40% of the ingested label was 
1974  absorbed (based on fecal excretion data) (Patriarca et al. 1997). In another study assessing the 
1975  effect of food on nickel absorption, between 2-23% of an administered dose was absorbed 
1976  (Nielsen et al, 1999). Therefore, on the basis of limited oral bioavailability of nickel and water-
1977  soluble nickel compounds, the parenteral PDE was calculated by dividing the oral PDE by a 
1978  modifying factor of 10 (as described in section 3.1). 
1979   
1980  PDE = 220 g/d / 10 = 22 g/day 
1981   
1982  PDE  Inhalation Exposure 
1983  For calculation of the inhalation PDE, a relevant form of nickel was selected from the available 
1984  data. In 2-year studies with nickel oxide, no tumors were observed in hamsters (Wehner et al. 
1985  1984) or mice (NTP, 2006). There was some evidence of carcinogenicity in rats (NTP, 2006) but 
1986  no evidence of carcinogenicity with inhalation of metallic nickel (Oller et al, 2008). For nickel, 
1987  the modifying factor approach was considered acceptable because the forms and levels likely to be 
1988  in inhalation drug products have not shown evidence of carcinogenicity. Taking into account the 
1989  modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated based on 
1990  the NOAEL in the rat study of 0.5 mg Ni/m3 /day. 
1991   
1992  For continuous dosing  = 0.5 mg/m3 x 6 hr/d x 5 d/wk = 0.089 mg/m3 = 0.000089 mg/L 
1993          24 hr/d x 7 d/wk  1000L/m3 
1994   
1995  Daily dose   =  0.000089 mg/L x 290 L/d   =   0.060 mg/kg 
1996          0.425 kg bw 
1997   
1998  PDE = 0.060 mg/kg x 50 kg / (5 x 10 x 1 x 10 x 1) = 6.0 g/day 
1999   
2000  A factor of ten was chosen for F4 because of the potential of relatively insoluble forms of Ni to 
2001  accumulate in the lungs and that inflammation was observed in the lungs upon histopathology 
2002  after inhalation of all forms of Ni. 
2003   
2004  REFERENCES 
2005  ATSDR. Toxicological profile for nickel. Agency for Toxic Substances and Disease Registry, 
2006  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2005. 
2007  Benson J, Chang I-Y, Cheny YS, Hahn FF, Kennedy CH et al. Fundam Appl Toxicol 
2008  1995;28:232-244. 
  60  Contains Nonbinding Recommendations 
 
2009  EU EFSA. Opinion of the scientific panel on dietetic products, nutrition and allergies on a 
2010  request from the Commission related to the tolerable upper intake level of nickel. European Food 
2011  Safety Authority. EFSA Journal 2005;146:1-21. 
2012  Haney JY, McCant DD, Sielken RL, Valdez-Flores C, Grant RL. Development of a unit risk 
2013  factor for nickel and inorganic nickel compounds based on an updated carcinogenicity toxicity 
2014  assessment. Reg Toxicol Pharmacol 2012;62:191-201. 
2015  Heim KE, Bates HK, Rush RE, Oller AR. Oral carcinogenicity study with nickel sulphate 
2016  hexahydrate in Fischer 344 rats. Toxicol Sci 2007;224:126-37. 
2017  IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on the 
2018  Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 
2019  World Health Organization, Lyon. 2012;100C. 
2020  Nielsen GD, Sderberg U, Jrgensen 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 B6C3F mice (inhalation studies). National Toxicology Program, U.S. Department of 
1 
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  Schaumloffel D. Nickel species:analysis and toxic effects. J Trace Elements Med Biol 
2033  2012;26:1-6. 
2034  Stockmann-Juvala H, Hedberg Y, Dhinsa NK, Griffiths DR, Brooks PN et al. Inhalation toxicity of 
2035  316L stainless steel powder in relation to bioaccessibility. Human Exp Toxicol 
2036  2013;32(11):1137-1154. 
2037  US EPA. Nickel, soluble salts (CASRN various). Integrated Risk Information System (IRIS). 
2038  1996. US EPA. Nickel refinery dust (no CASRN). Integrated Risk Information System (IRIS). 
2039  2012. 
2040  Wehner AP, Dagle GE, Busch RH. Pathogenicity of inhaled nickel compounds in hamsters. 
2041  IARC Sci Publ 1984;(53):143-51.   
  61  Contains Nonbinding Recommendations 
 
2042  PALLADIUM 
2043   
2044  Summary of PDE for Palladium 
Palladium (Pd) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  100  10  1.0 
2045   
2046  Introduction 
2047  Palladium (Pd) is a steel-white, ductile metallic element resembling and occurring with the other 
2048  platinum group metals and nickel. It exists in three states: Pd(0) (metallic), Pd(2+) and Pd(4+). It 
2049  can form organometallic compounds, only few of which have found industrial uses. Palladium 
2050  (on various supports) is being used as catalyst in hydrogenation reactions. Palladium metal is 
2051  stable in air and resistant to attack by most reagents except aqua regia and nitric acid. 
2052   
2053  Safety Limiting Toxicity 
2054  In a 90-day study in male rats administered 10, 100 and 250 ng/mL palladium in drinking water, 
2055  palladium was found to accumulate in the kidney but not liver, lung, spleen, or bones. 
2056  Elimination was primarily through the fecal route (Iavicoli et al, 2010). Several in vitro 
2057  mutagenicity tests of different palladium compounds with bacterial or mammalian cells (Ames 
2058  test with Salmonella typhimurium; SOS chromotest with Escherichia coli; micronucleus test with 
2059  human lymphocytes) gave negative results (IPCS, 2002; Kielhorn et al, 2002). The data was 
2060  reviewed to identify the safety limiting toxicities based on routes of administration. 
2061   
2062  PDE  Oral Exposure 
2063  Several long-term animal studies have been conducted exploring the toxicity and carcinogenicity 
2064  of palladium salts. However, none to date have been executed in accordance with current 
2065  guidelines for toxicological studies. The available data suggest potential NOAELs for palladium 
2066  in the range of 0.8-1.5 mg/kg. A lifetime study with mice given Pd(2+) chloride in drinking-
2067  water at a dose of about 1.2 mg Pd/kg/day found a significantly higher incidence of amyloidosis 
2068  in several inner organs of males and females and suppressed growth in males, but not in females 
2069  (Schroeder and Mitchener, 1971; IPCS, 2002). This study also contained a signal that suggested 
2070  a possible carcinogenic endpoint; however, the design of the study (single dose level, pooling of 
2071  the tumor rates from male and female animals, and a significant increase in the age of the treated 
2072  vs control animals) limited the utility of the data to assess the carcinogenic potential. Taking into 
2073  account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated 
2074  based on the LOEL of 1.2 mg/kg/day. 
2075   
2076  PDE = 1.2 mg/kg/d x 50 kg / (12 x 10 x 1 x 1 x 5) = 0.1 mg/d = 100 g/day 
2077   
2078  A factor of five was chosen for F5 because a LOEL was used in deriving the PDE. 
2079   
2080  PDE  Parenteral Exposure 
2081  The safety review for palladium was unable to identify any significant assessments upon which 
2082  to calculate a PDE for parenteral routes of exposure. Pd(2+) chloride (PdCl ) was poorly 
2
2083  absorbed from the digestive tract (<0.5% of the initial oral dose in adult rats or about 5% in 
  62  Contains Nonbinding Recommendations 
 
2084  suckling rats after 3-4 days). Absorption/retention in adult rats was higher following intratracheal 
2085  or intravenous exposure, resulting in total body burdens of 5% or 20%, respectively, of the dose 
2086  administered, 40 days after dosing (IPCS, 2002). On the basis of limited oral bioavailability of 
2087  palladium, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 
2088  10 (as described in section 3.1). 
2089   
2090  PDE = 100 g/d / 10 = 10 g/day 
2091   
2092  PDE  Inhalation Exposure 
2093  There are no adequate inhalation data on Pd. Therefore, the inhalation PDE was calculated by 
2094  dividing the oral PDE by a modifying factor of 100 (as described in section 3.1). 
2095   
2096  PDE = 100 g/d / 100 = 1.0 g/day 
2097   
2098  REFERENCES 
2099  Iavicoli I, Bocca B, Fontana L, Caimi S, Bergamaschi A, Alimonti A. Distribution and 
2100  elimination of palladium in rats after 90-day oral administration. Toxicol Ind Health 2010;26. 
2101  IPCS. Palladium. Environmental Health Criteria 226. International Programme on Chemical 
2102  Safety. World Health Organization, Geneva. 2002. 
2103  Kielhorn J, Melver C, Keller D, Mangelsdorf I. Palladium  a review of exposure and effects to 
2104  human health. Int J Hyg Environ Health 2002;205:417-432. 
2105  Schroeder HA, Mitchener M. Scandium, chromium (VI), gallium, yttrium, rhodium, palladium, 
2106  indium in mice: Effects on growth and life span. J Nutr 1971;101:1431-8.   
  63  Contains Nonbinding Recommendations 
 
2107  PLATINUM 
2108   
2109  Summary of PDE for Platinum 
Platinum (Pt) 
  Oral  Parenteral  Inhalation 
PDE (g/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 (H O) ]2+. The most common Pt IV catalysts are chloroplatinate salts 
2 4
2119  such as tetra and hexachloroplatinate ions. 
2120   
2121  Safety Limiting Toxicity 
2122  No experimental data are available on the carcinogenicity of platinum and platinum compounds 
2123  forms likely to be present in pharmaceuticals as impurities, and toxicology data are limited (US 
2124  EPA, 2009). 
2125  Chlorinated salts of platinum are responsible for platinum related hypersensitivity and are a 
2126  major occupational health concern (US EPA, 2009). The hypersensitivity appears to be the most 
2127  sensitive endpoint of chloroplatinate exposure, at least by the inhalation route. Signs include 
2128  urticaria, contact dermatitis of the skin, and respiratory disorders ranging from sneezing, shortness 
2129  of breath, and cyanosis to severe asthma (IPCS, 1991). Exposure reduction was effective in 
2130  resolving symptoms (Merget et al, 2001). Neutral complexes and complexes without 
2131  halogenated ligands do not appear allergenic (US EPA, 2009; EU SCOEL, 2011). The risk of 
2132  hypersensitivity appears to be related to sensitizing dose and dose and length of exposure (IPCS, 
2133  1991; US EPA, 2009; Arts et al, 2006) and cigarette smoking (US EPA, 2009; Merget et al, 
2134  2000; Caverley et al, 1995). The data was reviewed to identify the safety limiting toxicities 
2135  based on routes of administration 
2136   
2137  PDE  Oral Exposure 
2138  In a study in male rats administered PtCl (relatively insoluble) and PtCl (soluble) in the diet for 
2  4 
2139  4 weeks, no effects were observed on hematological and clinical chemistry parameters for PtCl . 
2
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 PtCl , the highest 
4
2142  dose tested. Platinum concentrations increased in tissues in animals dosed with either compound, 
2143  particularly the kidney (Reichlmayr-Lais et al, 1992). This study was used in the determination 
2144  of the PDE because toxicity is observed in the kidney with platinum compounds and was a main 
2145  site of accumulation in this study. Taking into account the modifying factors (F1-F5 as discussed 
2146  in Appendix 1), the oral PDE is calculated based on the NOAEL of 10 mg Pt/kg diet (4.1 mg Pt 
2147  taken over 28 days; 0.146 mg/d). The body weight of the rats was 35 g at the beginning of the 
  64  Contains Nonbinding Recommendations 
 
2148  study and the average weight gain over the course of the study was 235 g. A mean body weight 
2149  of 135 g was used in the calculation. 
2150   
2151  0.146 mg/d / 0.135 kg = 1.08 mg/kg/day 
2152   
2153  PDE = 1.08 mg/kg/d x 50 kg / (5 x 10 x 10 x 1 x 1) = 108 g/day 
2154   
2155  PDE  Parenteral Exposure 
2156  The safety review for platinum identified limited assessments of platinum salt toxicity for 
2157  parenteral routes of administration. The oral absorption of platinum salts is very low in rats (<1% 
2158  when administered by gavage) and higher in humans (42-60% of dietary Pt; US EPA, 2009). 
2159  Therefore, the oral PDE is divided by a factor of 10 (as described in section 3.1) to obtain the 
2160  parenteral PDE. 
2161   
2162  PDE = 108 g/d / 10 = 10.8 g/day 
2163   
2164  PDE  Inhalation Exposure 
2165  Due to the use of the chloroplatinates in catalytic converters, numerous animal (Biagini et al, 
2166  1983) and human (Pepys et al, 1972; Pickering 1972; Merget et al, 2000; Cristaudo et al., 2007) 
2167  studies have been conducted. The US EPA (1977; 2009) and the European Scientific Committee 
2168  on Occupational Exposure Limits (EU SCOEL, 2011) have also examined the safety of 
2169  chloroplatinates based on sensitization. The European Scientific Committee on Occupational 
2170  Exposure Limits (EU SCOEL) concluded that the database does not allow for setting an 
2171  occupational limit for soluble platinum salts. The US DoL (2013) has established an 
2172  occupational limit for soluble platinum salts at 2 g/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 g/m3 x 8 hr/d x 5 d/wk = 0.48 g/m3 = 0.00048 g/L 
2176          24 hr/d x 7 d/wk       1000 m3/L 
2177   
2178  Daily dose   =  0.00048 g/L x 28800 L/d = 0.27 g/kg/day 
2179             50 kg 
2180   
2181  PDE = 0.27 g/kg/d x 50 kg / (1 x 10 x 1 x 1 x 1) = 1.4 g/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, Na PtCl . Toxicol Appl Pharmacol 1983;69:377-84. 
2 6
2189  Caverley AE, Rees D, Dowdeswell RJ, Linnett PJ, Kielkowski D. Platinum salt sensitivity in 
2190  refinery workers: incidence and effects of smoking and exposure. Int J Occup Environ Med 
2191  1995;52:661-66. 
  65  Contains Nonbinding Recommendations 
 
2192  Cristaudo A, Picardo M, Petrucci F, Forte G, Violante N, Senofonte O et al. Clinical and 
2193  allergological biomonitoring of occupational hypersensitivity to platinum group elements. Anal 
2194  Lett 2007;40:3343-59. 
2195  EU SCOEL. Recommendation from the scientific committee on occupational exposure limits for 
2196  platinum and platinum compounds. European Union Scientific Committee on Occupational 
2197  Exposure Limits. 2011;SCOEL/SUM/150. 
2198  IPCS. Platinum. Environmental Health Criteria 125. International Programme on Chemical 
2199  Safety.  World Health Organization, Geneva. 1991. 
2200  Merget R; Kulzer R; Dierkes-Globisch A, Breitstadt R, Gebler A, Kniffka A, Artelt S, Koenig HP, 
2201  Alt F, Vormberg R, Baur X, Schultze-Werninghaus G. Exposure-effect relationship of platinum 
2202  salt allergy in a catalyst production plant: conclusions from a 5-year prospective cohort study. J 
2203  Allergy Clin Immunol 2000;105:364-370. 
2204  Merget R, Caspari C, Kulzer SA, Dierkes-Globisch R, Kniffka A, Degens P et al. Effectiveness 
2205  of a medical surveillance program for the prevention of occupational asthma caused by platinum 
2206  salts: a nested case control study. J Allergy Clin Immunol 2001;107:707-12. 
2207  Pepys J, Pickering CAC, Hughes EG. Asthma due to inhaled chemical agents--complex salts of 
2208  platinum. Clin Exp Allergy 1972;2:391-96. 
2209  Pickering CAC. Inhalation tests with chemical allergens: complex salts of platinum. Proc R Soc 
2210  Med 1972;65:2-4. 
2211  Reichlmayr-Lais AM, Kirchgessner M, Bader R. Dose-response relationships of alimentary PtCl
2 
2212  and PtCl in growing rats. J Trace Elem Electrolytes Health Dis 1992;6(3):183-7. 
4 
2213  US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
2214  Labor. 2013. 
2215  US EPA. Platinum-group metals. Environmental Health Effects Research Series 1977;EPA-
2216  600/1-77- 040. 
2217  US EPA. Toxicological review of halogenated platinum salts and platinum compounds. In 
2218  support of summary information on the Integrated Risk Information System (IRIS). 2009. 
2219  EPA/635/R-08/018   
  66  Contains Nonbinding Recommendations 
 
2220  Platinum-Group Elements 
2221   
2222  Summary of PDE for Platinum-Group Elements 
Iridium (Ir), Osmium (Os), Rhodium (Rh), Ruthenium (Ru) 
  Oral  Parenteral  Inhalation 
PDE (g/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 LD s are 
50
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. RuO appears to be a stronger 
4 
2230  oxidizing agent than OsO , at least when used in fixing tissues (Gaylarde and Sarkany, 1968; 
4
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    Iridium induced DNA single strand breaks in rat fibroblasts as measured in a 
o
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    Groups of Wistar rats were administered Ir(3+) chloride hydrate in drinking 
o
2244  water (0, 0.019, 0.19, 1.9, 9.5 and 19 g 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 g/d, this study was not adequate to set an oral 
2247  PDE. 
2248    Osmium 
2249    Osmium tetroxide is not very soluble in water (Luttrell and Giles, 2007). 
o
2250  Metallic osmium is not toxic (McLaughlin et al, 1946). 
2251    Osmium tetroxide has been used as a treatment for arthritis. As a vapor, OsO4 
o
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    The Permitted Exposure Limit (PEL) TWA for osmium tetroxide (as osmium) 
o
3 
2256  is 0.002 mg/m (UsD0L, 2013). 
2257    Rhodium 
  67  Contains Nonbinding Recommendations 
 
2258    Rh salts (K2RhCl5, (NH4)3RhCl6) were genotoxic in Salmonella typhimurium 
o
2259  (Bunger 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    In a lifetime carcinogenicity bioassay in mice administered rhodium chloride, a 
o
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    The PEL TWA for rhodium (as Rh) metal fume and insoluble compounds is 0.1 
o
3 3 
2272  mg/m . The PEL TWA for soluble compounds of Rh is 0.001 mg/m (UsD0L, 
2273  2013). 
2274    Ruthenium 
2275    Several Ru complexes cause genotoxic responses in vitro in Salmonella 
o
2276  typhimurium strains TA98 and TA100 (Monti-Bragadin et al, 1975; Yasbin et 
2277  al, 1980; Benkli et al, 2009). 
2278    Oral absorption of Ru is low (about 4%); the half-life of a parenteral dose is 
o
2279  about 200 days. Ingested ruthenium compounds are retained in bones (Furchner 
2280  et al, 1971). 
2281   
2282  REFERENCES 
2283  Benkli K, Tunali Y, Canturk S, Artagan O, Alanyali F. Cytotoxic and genotoxic effects of 
2284  [Ru(phi) ]2+ evaluated by Ames/Salmonella and MTT methods. Europ J Medic Chem 
3
2285  2009;44:2601-5. 
2286  Bunger J, Stork J, Stalder K. Cyto- and genotoxic effects of coordination complexes of platinum, 
2287  palladium and rhodium in vitro. Int Arch Occup Environ Health 1996;69(1):33-8. 
2288  Furchner JE, Richmond CR, Drake GA. Comparative Metabolism of Radionuclides in Mammals 
2289  - VII. Retention of 106Ru in the Mouse, Rat, Monkey and Dog. Health Phuysics 1971;21(3):355-
2290  65. 
2291  Gaylarde P, Sarkany I. Ruthenium tetroxide for fixing and staining cytoplasmic membranes. 
2292  Science 1968;161(3846):1157-8. 
2293  Goossens A, Cattaert N, Nemery B, Boey L, De Graef E. Occupational allergic contact dermatitis 
2294  caused by rhodium solutions. Contact dermatitis 2011;64:158-61. 
2295  Iavicoli I, Fontana L, Marinaccio A, Calabrese EJ, Alimonti M, Pino A et al. The effects of 
2296  iridium on the renal function of female Wistar rats. Ecotoxicol Environ Safety 2011;74:1795-9. 
  68  Contains Nonbinding Recommendations 
 
2297  Iavicoli I, Cufino V, Corbi M, Goracci M, Caredda E, Cittadini A et al. Rhodium and iridium salts 
2298  inhibit proliferation and induce DNA damage in rat fibroblasts in vitro. Toxicol in vitro 
2299  2012;26(6):963-9. 
2300  Luttrell WE, Giles CB. Toxic tips: Osmium tetroxide. J Chemical Health Safety 
2301  2007;Sept/Oct:40-1. 
2302  McLaughlin AIG, Milton R, Perry KMA. Toxic manifestations of osmium tetroxide. Brit J Ind 
2303  Med 1946;3:183-6. 
2304  Migliore L, Frenzilli G, Nesti C, Fortaner S, Sabbioni E. Cytogenic and oxidative damage 
2305  induced in human lymphocytes by platinum, rhodium and palladium compounds. Mutagenesis 
2306  2002;17:411-7. 
2307  Monti-Bragadin C, Tamaro M, Banfi E. Mtuagenic activity of platinum and tuthenium 
2308  complexes. Chem Biol Interact 1975;11:469-72. 
2309  Schroeder HA, Mitchener M. Scandium, chromium (VI), gallium, yttrium, rhodium, palladium, 
2310  indium in mice: Effects on growth and life span. J Nutr 1971;101:1431-8. 
2311  Swartzendruber DC, Burnett IH, Wertz PW, Madison KC, Squier CA. Osmium tetroxide and 
2312  ruthenium tetroxide are complementary reagents for the preparation of epidermal samples for 
2313  transmission electron microscopy. J Invest Dermatol 1995;104(3):417-20. 
2314  USDoL (OHSA). Occupational health guideline for osmium tetroxide. U.S. Department of 
2315  Labor. 1978. 
2316  USDoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
2317  Labor. 2013 
2318  Wiseman CLS, Sereini F. Airborne particulate matter, platinum group elements and human 
2319  health: A review of recent evidence. Sci Total Environ 20009;407:2493-500. 
2320  Yasbin RE, Matthews CR, Clarke MJ. Mutagenic and toxic effects of ruthenium. Chem Biol 
2321  Interact 1980:31:355-65.   
  69  Contains Nonbinding Recommendations 
 
2322  SELENIUM 
2323   
2324  Summary of PDE for Selenium 
Selenium (Se) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  170  85  135 
2325   
2326  Introduction 
2327  Selenium (Se) is present in the earth's crust, often in association with sulfur-containing minerals. 
2328  It can assume four oxidation states (-2, 0, +4, +6) and occurs in many forms, including elemental 
2329  selenium, selenites and selenates. Selenium is an essential trace element for many species, 
2330  including humans. Selenium is incorporated into proteins via a specific selenocysteine tRNA. 
2331  Selenium is being used as a catalyst in the manufacture of rubber. Ru-Se catalysts are used in 
2332  oxygen reduction. Aryl- and alkyl- Selenium reagents have various applications in organic 
2333  synthesis. 
2334   
2335  Safety Limiting Toxicity 
2336  Selenium was listed as a Group 3 compound (not classifiable for carcinogenesis) by IARC 
2337  (1987). The only selenium compound that has been shown to be carcinogenic in animals is 
2338  selenium sulfide (NTP, 1980). According to the US EPA, selenium sulfide is in Group B2 
2339  (probable human carcinogen) (US EPA, 2002). Other selenium compounds are classified as D; 
2340  not classifiable as to carcinogenicity in humans. 
2341  The most significant toxicity observed with excessive exposure in humans to Se is selenosis, 
2342  characterized primarily by dermal and neurological effects, including unsteady gait and paralysis 
2343  (ATSDR, 2003). There is some concern over exposure to excessive levels of selenium in the diet; 
2344  to limit the total exposure to Se, various organizations have set an upper tolerable limit at 400 
2345  g/day (WHO, 2011). Occupational studies describe respiratory effects such as irritation of the 
2346  nose, respiratory tract, and lungs, bronchial spasms, and coughing following chronic exposure to 
2347  selenium dioxide or elemental selenium as dust. Respiratory symptoms similar to those reported 
2348  for occupationally-exposed humans have been seen in animals inhaling high doses of elemental 
2349  selenium fumes or dust, and studies of animals with acute inhalation exposure to hydrogen 
2350  selenide or elemental selenium fumes or dust have reported hepatocellular degeneration and 
2351  atrophy of the liver. Absorption after inhalation exposure is uncertain (ATSDR, 2003). 
2352   
2353  PDE  Oral Exposure 
2354  In a rat carcinogenicity study of selenium sulfide, the NOAEL for hepatocellular carcinoma was 3 
2355  mg/kg/day (1.7 mg Se/kg/day) (NTP, 1980). Although, there is insufficient data to assess 
2356  carcinogenicity of other forms of selenium, and the human relevance of the rodent liver tumors has 
2357  been questioned (IARC, 1999), this is the best available study. Some human data are available but 
2358  only in a limited number of subjects (ATSDR, 2003). The calculated PDE is in line with the MRL 
2359  of 5 g/kg/day for Se (ATSDR, 2003). Taking into account the modifying factors (F1-F5 as 
2360  discussed in Appendix 1), the oral PDE is calculated as below. 
2361   
2362  PDE = 1.7 mg/kg/d x 50 kg / (5 x 10 x 1 x 10 x 1) = 170 g/day 
2363   
  70  Contains Nonbinding Recommendations 
 
2364  A factor of ten was chosen for F4 because of the risk of selenosis. 
2365   
2366  PDE  Parenteral Exposure 
2367  Studies in humans and experimental animals indicate that, when ingested, several selenium 
2368  compounds including selenite, selenate, and selenomethionine are readily absorbed, often to 
2369  greater than 80% of the administered dose (ATSDR, 2003). On the basis of oral bioavailability of 
2370  ~80%, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 
2371  (as described in section 3.1). 
2372   
2373  PDE = 170 g/d / 2 = 85 g/day 
2374   
2375  PDE  Inhalation Exposure 
2376  Respiratory endpoints are the most sensitive markers for inhalation exposure in occupational 
2377  studies. Occupational limits have established time weighted averages for selenium exposures of 
2378  0.2 mg/m3 (US DoL, 2013) and 0.07 by the European Union Scientific Expert Group (EU SEG, 
2379  1992). However, the EU SEG Occupation Exposure Limits (OEL) was based on hydrogen 
2380  selenide, a form not likely to be present in inhalation products. Thus, using the OEL derived by 
2381  US DoL, and taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the 
2382  inhalation PDE is calculated as below. 
2383   
2384  For continuous dosing = 0.2 mg/m3 8 hr/d x 5 d/wk = 0.048 mg/m3 = 0.000048 mg/L 
2385    24 hr/d x 7 d/wk  1000 L/m3 
2386   
2387  Daily dose  =     0.000048 mg/L x 28800 L =  0.027 mg/kg   
2388  50 kg 
2389   
2390  PDE = 0.027 mg/kg x 50 kg / (1 x 10 x 1 x 1 x 1) = 0.135 mg/day =135 g/day 
2391   
2392  REFERENCES 
2393  ATSDR. Toxicological profile for selenium. Agency for Toxic Substances and Disease Registry, 
2394  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2003. 
2395  EU SEG. Recommendation from the Scientific Expert Group on Occupation Exposure Limits for 
2396  Hydrogen selenide. European Union Scientific Expert Group. 1992;SEG/SUM/22C 
2397  IARC. Overall evaluations of carcinogenicity: An update of IARC monographs volumes 1 to 42. 
2398  Monographs on the Evaluation of the Carcinogenic Risks to Humans. International Agency for 
2399  Research on Cancer, World Health Organization, Lyon. 1987;Suppl 7. 
2400  IARC. Some aziridines, N-, S- and O-mustards and selenium. Summary of data reported and 
2401  evaluation. Monographs on the Evaluation of Carcinogenic Risks to Humans. International 
2402  Agency for Research on Cancer, World Health Organization, Lyon. 1999. 
2403  NTP. Bioassay of selenium sulfide (gavage) for possible carcinogenicity. National Toxicology 
2404  Program, US Department of Health and Human Services. 1980;Technical Report Series No 194. 
2405  US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
2406  Labor. 2013. 
  71  Contains Nonbinding Recommendations 
 
2407  US EPA. Selenium and compounds (CAS No. 7782-49-2). Integrated Risk Information System 
2408  (IRIS). 2002. 
2409  WHO. Selenium in Drinking-water; Background document for development of WHO Guidelines 
2410  for Drinking-water Quality. World Health Organization, Geneva. 2011. 
2411  WHO/HSE/WSH/10.01/14   
  72  Contains Nonbinding Recommendations 
 
2412  SILVER 
2413   
2414  Summary of PDE for Silver 
Silver (Ag) 
  Oral  Parenteral  Inhalation 
PDE (g/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 10100 
2421  g/kg range. Silver is nutritionally not essential, and no metabolic function is known. Silver is 
2422  being used as a catalyst in the oxidation of ethylene to ethylene oxide. Silver-Cadmium alloy is 
2423  used in selective hydrogenation of unsaturated carbonyl compounds. Silver oxide is used as a 
2424  mild oxidizing agent in organic synthesis. 
2425   
2426  Safety Limiting Toxicity 
2427  Silver is not mutagenic. Animal toxicity studies and human occupational studies have not 
2428  provided sufficient evidence of carcinogenicity. Based on these data silver is not expected to be 
2429  carcinogenic in humans (ATSDR, 1990). 
2430  Argyria appears to be the most sensitive clinical effect in response to human Ag intake. Silver 
2431  acetate lozenges are used in smoking cessation (Hymowitz and Eckholdt, 1996). Argyria, a 
2432  permanent bluish- gray discoloration of the skin, results from the deposition of Ag in the dermis 
2433  combined with a silver- induced production of melanin. Inhalation of high levels of silver can 
2434  result in lung and throat irritation and stomach pains (ATSDR, 1990). 
2435   
2436  PDE  Oral Exposure 
2437  Silver nitrate was added at 0.015% to the drinking water of female mice (0.9 g/mouse; 32.14 
2438  mg/kg silver nitrate; 64% silver) for 125 days to examine neurobehavioral activity of the animals 
2439  based on potential neurotoxicity of silver (Rungby and Danscher, 1984). Treated animals were 
2440  hypoactive relative to controls; other clinical signs were not noted. In a separate study, silver was 
2441  shown to be present in the brain after mice were injected with 1 mg/kg intra peritoneal silver 
2442  lactate (Rungby and Danscher, 1983). The oral PDE is consistent with the reference dose of 5 
2443  g/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 g/day 
2447   
2448  A factor ten was chosen for F5 because the LOAEL was used to set the PDE as few toxicological 
2449  endpoints were examined. 
2450   
2451  PDE  Parenteral Exposure 
2452  The safety review for silver identified one study in humans by the intravenous route published by 
2453  Gaul and Staud in 1935. In this study silver arsphenamine was administered intravenously to 12 
2454  patients in 31-100 injections over 2 to 9.75 years. Based on cases presented in the study, the 
  73  Contains Nonbinding Recommendations 
 
2455  lowest cumulative dose of silver resulting in argyria was 1 g metallic silver. Argyria was reported 
2456  in other patients at higher cumulative doses of silver. Using this study, the US EPA (2003) 
2457  identified this dose as a LOAEL. This study was considered inadequate to set a parenteral PDE 
2458  as it involved few patients and the dosing was not adequately described. However, the study was 
2459  useful in that it identified argyria as a result of cumulative dosing. 
2460   
2461  Silver is known to be absorbed across mucosal surfaces. Absorption of silver acetate occurred 
2462  after ingestion of a dose of radiolabelled silver with approximately 21% of the dose being 
2463  retained at 1 week (ATSDR, 1990). In a review of the oral toxicity of silver, Hadrup and Lam 
2464  (2014) report that absorption of a radionuclide of silver (as silver nitrate) was between 0.4 to 
2465  18%, depending upon the species, with humans at 18%. On the basis of an oral bioavailability 
2466  between 1% and 50% for silver, the parenteral PDE was calculated by dividing the oral PDE by a 
2467  modifying factor of 10 (as described in section 3.1). The recommended PDE for silver for 
2468  parenteral exposure is: 
2469   
2470  PDE = 167 g/d / 10 = 16.7 g/day 
2471   
2472  PDE  Inhalation Exposure 
2473  Lung and throat irritation and stomach pains were the principal effects in humans after inhalation 
2474  of high Ag levels. Using the Threshold Limit Value (TLV) of 0.01 mg/m3 for silver metal and 
2475  soluble compounds (US DoL, 2013), and taking into account the modifying factors (F1-F5 as 
2476  discussed in Appendix 1), the inhalation PDE is calculated as: 
2477   
2478  For continuous dosing = 0.2 mg/m3 8 hr/d x 5 d/wk = 0.048 mg/m3 = 0.000048 mg/L 
2479    24 hr/d x 7 d/wk  1000 L/m3 
2480   
2481  Daily dose  =     0.000048 mg/L x 28800 L =  0.027 mg/kg   
2482  50 kg 
2483   
2484  PDE = 0.027 mg/kg x 50 kg / (1 x 10 x 1 x 1 x 1) = 0.135 mg/day =135 g/day 
2485   
2486  REFERENCES 
2487  ATSDR. Toxicological Profile for Silver. Agency for Toxic Substances and Disease Registry, 
2488  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1990. 
2489  Gaul LE, Staud AH. Clinical spectroscopy. Seventy cases of generalized argyrosis following 
2490  organic and colloidal Ag medication. JAMA. 1935, 104:13871390. 
2491  Hadrup N, Lam HR. Oral toxicity of silver ions, silver nanoparticles and colloidal silver - A 
2492  review. Regul Toxicol Pharmacol. 2014 68(1):1-7. 
2493  Hymowitz N, Eckholt H. Effects of a 2.5-mg silver acetate lozenge on initial and long-term 
2494  smoking cessation. Prev Med 1996;25:537-46. 
2495  Rungby J, Danscher G. Hypoactivity in silver exposed mice. Acta Pharmacol Toxicol 
2496  1984;55:398-401. 
2497  Rungby J, Danscher G. Localization of exogenous silver in brain and spinal cord of silver 
2498  exposed rats. Acta Neuropathol 1983;60(1-2):92-8. 
  74  Contains Nonbinding Recommendations 
 
2499  US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
2500  Labor. 2013. 
2501  US EPA. Silver (CASRN 7440-22-4). Integrated Risk Information System (IRIS). 2003.   
  75  Contains Nonbinding Recommendations 
 
2502  THALLIUM 
2503   
2504  Summary of PDE for Thallium 
Thallium (Tl) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  8.0  8.0  8.0 
2505   
2506  Introduction 
2507  Pure thallium (Tl) is a bluish-white metal. It exists primarily in two oxidation states: +1 and +3. 
2508  Monovalent thallium is similar to potassium (K+) in ionic radius and electrical charge, which 
2509  contributes to its toxic nature. Many of the thallium salts are soluble in water with the exception 
2510  of the insoluble Tl(3+) oxide. Thallium sulfate has been used in medicine, primarily as a 
2511  depilatory agent, but also to treat infections, such as venereal diseases, ringworm of the scalp, 
2512  typhus, tuberculosis, and malaria. Tl(3+) salts are being used in organic synthesis. Thallium is 
2513  nutritionally not essential and no metabolic function is known (ATSDR, 1992). 
2514   
2515  Safety Limiting Toxicity 
2516  In humans and animals, the skin, especially the hair follicles, appears to be the most sensitive 
2517  target of toxicity from repeated oral exposure to thallium (US EPA, 1992; US EPA, 2009). Water 
2518  soluble salts (sulphate, acetate, or carbonate) have higher toxicity than other forms (Moore et al, 
2519  1993). 
2520   
2521  PDE  Oral Exposure 
2522  The primary target organ for oral exposure to thallium in humans and animals appears to be the 
2523  skin, especially the hair follicles, as shown in a 90-day toxicity rat study with thallium sulfate. 
2524  The NOAEL was defined at 0.04 mg Tl/kg on the basis of an increased incidence of alopecia at 
2525  the higher doses (OEHHA, 1999; US EPA, 2009). Thus, the oral PDE was determined on the 
2526  basis of the NOAEL of 0.04 mg Tl/kg in rat. 
2527  Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is 
2528  calculated as below. 
2529   
2530  PDE = 0.04 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 0.008 mg/day = 8.0 g/day 
2531   
2532  PDE  Parenteral Exposure 
2533  No relevant data on parenteral exposure to thallium compounds were found. The bioavailability 
2534  of soluble thallium salts is high (> 80%) (US EPA, 2009). Therefore, the parenteral PDE is the 
2535  same as the oral PDE. 
2536   
2537  PDE = 8.0 g/day 
2538   
2539  PDE  Inhalation Exposure 
2540  No relevant data on inhalation exposure to thallium compounds were found. The US EPA 
2541  concluded that information on the inhalation toxicity of thallium is insufficient to derive an 
2542  inhalation reference concentration. Occupational epidemiology studies involving possible 
2543  inhalation exposures to thallium were limited and inconclusive (US EPA, 2009). The major 
  76  Contains Nonbinding Recommendations 
 
2544  toxicity identified in humans and animals is alopecia, and absorption and toxicity is considered 
2545  high by the inhalation route (IPCS, 1996). Similar findings may be expected by Tl exposure via 
2546  oral and respiratory routes. For this reason, the inhalation PDE is set at the parenteral PDE. 
2547   
2548  PDE = 8.0 g/day 
2549   
2550  REFERENCES 
2551  ATSDR. Toxicological profile for thallium. Agency for Toxic Substances and Disease Registry, 
2552  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1992. 
2553  IPCS. Thallium and thallium salts: health and safety guide. International Programme on 
2554  Chemical Safety, World Health Organization, Geneva, 1996. Health and Safety Guide No. 102. 
2555  Moore D, House I, Dixon A. Thallium poisoning. Br Med J 1993;306:1527-9. 
2556  OEHHA. Public health goal for thallium in drinking water. Office of Environmental Health 
2557  Hazard Assessment, Berkeley and Sacramento, CA. 1999. 
2558  US EPA. Drinking water criteria document for thallium. Health and Ecological Criteria Division; 
2559  Office of Science and Technology; Office of Water; U.S. Environmental Protection Agency, 
2560  Washington DC, 1992. 
2561  US EPA. Toxicological review of thallium and compounds (CAS No. 7440-28-0). Integrated 
2562  Risk Information System (IRIS). 2009. EPA/635/R-08/001F   
  77  Contains Nonbinding Recommendations 
 
2563  TIN 
2564   
2565  Summary of PDE for Tin 
Tin (Sn) 
  Oral  Parenteral  Inhalation 
PDE (g/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 g Sn/tablet). Tin is possibly nutritionally essential for some animals, but it has not been 
2572  shown to be essential for humans. Tin(2+) chloride is being used as a reducing agent, and as a 
2573  stabilizer of polyvinylchloride (PVC). This safety assessment focuses on inorganic tin 
2574  considering that the more frequent occurrence of inorganic tin is more relevant with respect to 
2575  metal impurities in drug products than organic tin compounds. 
2576   
2577  Safety Limiting Toxicity 
2578  There is no indication of in vivo genotoxicity or carcinogenicity for tin and tin salts. In several 
2579  studies in rats, a decrease in hemoglobin as an early sign for anemia was the most sensitive 
2580  endpoint. In general, in in vitro assays tin and tin salts were negative for mutagenicity but some 
2581  forms were positive for chromosomal damage (CICAD, 2005). Stannous chloride was not 
2582  carcinogenic in the two-year assay in mice or rats (NTP, 1982). 
2583   
2584  PDE  Oral Exposure 
2585  Anemia was the most sensitive endpoint in rats after repeated oral administration. Thus, the PDE 
2586  for oral exposure was determined on the basis of the lowest NOAEL, i.e., 150 ppm (equivalent to 
2587  32 mg Sn/kg/day; ATSDR, 2005). This value was obtained from a 90-day study in rats based on 
2588  signs of anemia starting at 500 ppm in rats exposed to stannous chloride via diet (de Groot et al, 
2589  1973). This study was considered more relevant than the NTP study (NTP, 1982) in determining 
2590  the oral PDE because in the 13-week NTP dose range finding study, the toxicological evaluation 
2591  was more limited (e.g., no clinical chemistry, including effects on hemoglobin) than in the study 
2592  by de Groot et al. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), 
2593  the oral PDE is calculated as below. 
2594   
2595  PDE = 32 mg/kg/d x 50 kg / (5 x 10 x 5 x 1 x 1) = 6.4 mg/d = 6400 g/day 
2596   
2597  PDE  Parenteral Exposure 
2598  The safety review for tin was unable to identify any significant assessments upon which to 
2599  calculate a PDE for parenteral routes of exposure. On the basis of an oral bioavailability of about 
2600  5% for tin and inorganic tin compounds (ATSDR, 2005), the parenteral PDE was calculated by 
2601  dividing the oral PDE by a modifying factor of 10 (as described in section 3.1). 
2602   
2603  PDE = 6400 g/d / 10 = 640 g/day 
2604   
  78  Contains Nonbinding Recommendations 
 
2605  PDE  Inhalation Exposure 
2606  The safety review for tin was unable to identify any significant assessments on inorganic tin upon 
2607  which to calculate a PDE for inhalation routes of exposure. Although a TLV is available for tin 
2608  (2 mg/m3; US DoL, 2013), there is insufficient data to set a MRL (ATSDR 2005; EU SCOEL 
2609  2003). Therefore, the PDE for tin is calculated by using a factor of 100 to convert the oral PDE 
2610  to the inhalation PDE (as described in section 3.1). 
2611   
2612  PDE = 6400 g/d / 100 = 64 g/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 B6C3F /N mice (feed study). National Toxicology Program. U.S. Department of 
1
2627  Health and Human Services. 1982; Technical Report Series No. 231. 
2628  US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of 
2629  Labor. 2013.   
  79  Contains Nonbinding Recommendations 
 
2630  VANADIUM 
2631   
2632  Summary of PDE for Vanadium 
Vanadium (V) 
  Oral  Parenteral  Inhalation 
PDE (g/day)  120  12  1.2 
2633   
2634  Introduction 
2635  Vanadium (V) is present as a trace element in the earths 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 bein3g   vanadate, VO - an2 d 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 g/day. Intake from drinking water depends on the water source and 
2640  estimates are up to 140 g/day. Human populations have variable serum concentrations of 
2641  vanadium, with 2 g/L being the high end of the normal range. Despite its being ubiquitous in the 
2642  body, an essential biological role for vanadium in humans has not been established. 
2643   
2644  Safety Limiting Toxicity 
2645  Vanadium is genotoxic, but not mutagenic (ATSDR, 2012). Vanadium pentoxide is classified as 
2646  a possible human carcinogen (Group 2B; IARC, 2012). 
2647   
2648  PDE  Oral Exposure 
2649  Following oral administration to animals and humans the gastrointestinal tract, cardiovascular, 
2650  and hematological system are the primary targets of toxicity. The most appropriate study to assess 
2651  vanadium toxicity through oral administration was conducted in humans exposed to vanadium 
2652  for 12 weeks. In this study, no significant alterations in hematological parameters, liver function 
2653  (as measured by serum enzymes), cholesterol and triglyceride levels, kidney function (as 
2654  measured by blood urea nitrogen), body weight, or blood pressure were observed in subjects 
2655  administered via capsule 0.12 or 0.19 mg vanadium as ammonium vanadyl tartrate or vanadyl 
2656  sulfate for 612 weeks (ATSDR, 2012). The oral NOAEL of 0.12 mg vanadium/kg/day for 
2657  hematological and blood pressure effects was used to calculate the oral PDE. Taking into account 
2658  the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as below. 
2659   
2660  PDE = 0.12 mg/kg/d x 50 kg / (1 x 10 x 5 x 1 x 1) = 0.12 mg/d = 120 g/day 
2661   
2662  PDE  Parenteral Exposure 
2663  The safety review for vanadium was unable to identify any significant assessments upon which 
2664  to calculate a PDE for parenteral routes of exposure. On the basis of an approximate oral 
2665  bioavailability of <110% 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 g/day / 10 = 12 g/day 
2670   
  80  Contains Nonbinding Recommendations 
 
2671  PDE  Inhalation Exposure 
2672  A two-year chronic inhalation exposure study in rats was considered for use for the inhalation 
2673  PDE for vanadium. In this study, carcinogenic effects were observed to the lowest dose tested, 
2674  0.5 mg/m3 vanadium pentoxide (Ress et al. 2003). Vanadium pentoxide is a caustic agent and is 
2675  not considered to be present in drug products. Therefore, the inhalation PDE for vanadium was 
2676  calculated by dividing the oral PDE by a modifying factor of 100 (as described in section 3.1). 
2677   
2678  PDE = 120 g/d / 100 = 1.2 g/day 
2679   
2680  REFERENCES 
2681  ATSDR. Toxicological profile for vanadium. Agency for Toxic Substances and Disease Registry, 
2682  Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. 
2683  IARC. Arsenic, metals, fibers, and dusts: a review of human carcinogens. Monographs on the 
2684  Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer, 
2685  World Health Organization, Lyon. 2012;100C. 
2686  Ress NB, Chou BJ, Renne RA, Dill JA, Miller RA, Roycroft JH et al. Carcinogenicity of inhaled 
2687  vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicol Sci 2003;74(2):287-96.   
  81  Contains Nonbinding Recommendations 
 
2688  Appendix 4: Illustrative Examples 
2689   
2690  Examples for Converting PDEs into Permitted Elemental Impurity Concentrations 
2691   
2692  Option 1: Permitted common concentration limits of elemental impurities across drug product 
2693  component materials for products with daily intakes of not more than ten grams. 
2694  For this example, consider a solid oral drug product with a maximum daily intake of 2.5 grams, 
2695  containing nine components (1 drug substance and eight excipients, see Table A.4.1). Because this 
2696  drug product does not exceed a maximum daily intake of ten grams, the concentrations in Table 
2697  A.2.2 may be used. As Option 1 has a common permitted concentration, the nine components can 
2698  be used in any proportion in the formulation. The drug substance synthesis uses Pd and Ni 
2699  catalysts, and Pb, As, Cd, Hg, and V are also of concern on the basis of the risk assessment. The 
2700  maximum daily intake of each elemental impurity in the drug product is given in Table A.4.2 
2701  assuming that each elemental impurity is present at the concentration given in Table A.2.2. The 
2702  maximum potential daily intake of an elemental impurity is determined using the actual drug 
2703  product daily intake and the concentration limit for the elemental impurity in Table A.2.2 
2704  (concentration multiplied by the actual daily intake of the drug product of 2.5 grams). The 
2705  maximum daily intake given for each elemental impurity is not a summation of values found in 
2706  the individual columns of Table A.4.2. 
2707  This calculation demonstrates that no elemental impurities exceed their PDEs. Thus, if these 
2708  concentrations in each component are not exceeded, the drug product is assured to not exceed the 
2709  PDEs for each identified elemental impurity. 
2710   
2711  Table A.4.1: Maximum Daily Intake of Components of the Drug Product 
Component  Daily Intake, g 
Drug Substance  0.200 
Microcrystalline Cellulose (MCC)  1.100 
Lactose  0.450 
Ca Phosphate  0.350 
Crospovidone  0.265 
Mg Stearate  0.035 
Hydroxypropylmethyl Cellulose (HPMC)  0.060 
Titanium Dioxide  0.025 
Iron Oxide  0.015 
Drug Product  2.500 
2712   
2713  Table A.4.2: Permitted Concentrations from Table A.2.2 (assuming uniform 
2714  concentrations and 10 grams daily intake) 
  Maximum Permitted Concentration (g/g) 
Component 
Pb  As  Cd  Hg  Pd  V  Ni 
Drug Substance  0.5  1.5  0.5  3  10  10  20 
MCC  0.5  1.5  0.5  3  10  10  20 
Lactose  0.5  1.5  0.5  3  10  10  20 
Ca Phosphate  0.5  1.5  0.5  3  10  10  20 
Crospovidone  0.5  1.5  0.5  3  10  10  20 
  82  Contains Nonbinding Recommendations 
 
Mg Stearate  0.5  1.5  0.5  3  10  10  20 
HPMC  0.5  1.5  0.5  3  10  10  20 
Titanium  0.5  1.5  0.5  3  10  10  20 
Dioxide 
Iron Oxide  0.5  1.5  0.5  3  10  10  20 
Maximum Daily 
1.25  3.75  1.25  7.5  25  25  50 
intake (g) 
PDE (g)  5  15  5  30  100  100  200 
2715   
2716  Option 2a: Permitted common concentration limits across drug product component materials for 
2717  a product with a specified daily intake: 
2718  For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 
2719  grams, containing nine components (1 drug substance and eight excipients, see Table A.4.1) used 
2720  in Option 1. As Option 2a has a common permitted concentration, the nine components can be 
2721  used in any proportion in the formulation. The drug substance synthesis uses Pd and Ni catalysts, 
2722  Pb, As, Cd, Hg, and V are also of concern on the basis of the risk assessment. The maximum 
2723  concentration of each elemental impurity identified in the risk assessment can be calculated 
2724  using the PDEs in Table A.2.1 and Equation 1. 
2725  The maximum potential daily intake of an elemental impurity is determined using the actual drug 
2726  product daily intake and the concentration limit for the elemental impurity in Table A.4.3 
2727  (concentration multiplied by the actual daily intake of the drug product of 2.5 grams). The 
2728  maximum daily intake given for each elemental impurity is not a summation of values found in the 
2729  individual columns of Table A.4.3. 
2730  This calculation also demonstrates that no elemental impurities exceed their PDEs. Thus, if these 
2731  concentrations in each component are not exceeded, the drug product is assured to not exceed the 
2732  PDEs for each identified elemental impurity. 
2733  The factor of four increase in Option 2a for permitted concentration seen when comparing 
2734  Option 1 and Option 2a concentration limits is due to the use of ten grams and 2.5 grams, 
2735  respectively, as daily intake of the drug product. 
2736   
2737  Table A.4.3: Calculation of Maximum Permitted Concentrations Assuming Uniform 
2738  Concentrations in a Product with a Specified Daily Intake: 
2739 
 
  Maximum Permitted Concentration (g/g) 
Component 
Pb  As  C Hg  Pd  V  Ni 
d 
Drug Substance  2  6  2  12  40  40  80 
MCC  2  6  2  12  40  40  80 
Lactose  2  6  2  12  40  40  80 
Ca Phosphate  2  6  2  12  40  40  80 
Crospovidone  2  6  2  12  40  40  80 
Mg Stearate  2  6  2  12  40  40  80 
HPMC  2  6  2  12  40  40  80 
  83  Contains Nonbinding Recommendations 
 
Titanium Dioxide  2  6  2  12  40  40  80 
Iron Oxide  2  6  2  12  40  40  80 
Maximum Daily 
5  15  5  30  100  100  200 
intake (g) 
PDE (g)  5  15  5  30  100  100  200 
2740   
2741   
2742  Option 2b: Permitted concentration limits of elemental impurities across drug product 
2743  component materials for a product with a specified daily intake: 
2744  For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 
2745  grams, containing nine components (1 drug substance and eight excipients, see Table A.4.1) used 
2746  in Option 1 and 2a. The drug substance synthesis uses Pd and Ni catalysts, and Pb, As, Cd, Hg, 
2747  and V are also of concern on the basis of the risk assessment. To use Option 2b, the composition 
2748  of the drug product and additional knowledge regarding the content of each elemental impurity in 
2749  the components of the drug product are considered. The following table shows example data on 
2750  elemental impurities that may be derived from the sources described in section 5.5: 
2751   
2752  Table A.4.4: Concentrations of Elemental Impurities (g/g) in the Components 
  Concentration (g/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 
20  1  1  1  *  1  <LoQ 
Dioxide 
Iron Oxide  10  10  10  10  *  2000  50 
2753  * = The risk assessment determined that Pd was not a potential elemental impurity; a quantitative 
2754  result was not obtained. 
2755  Using the information presented in Table A.4.4, one can evaluate different sets of potential 
2756  concentrations for each elemental impurity in each component. In table A.4.5, an example of one 
2757  set of these concentrations is displayed. In this case, a high concentration of lead has been 
2758  allocated to titanium dioxide and the PDE would not be exceeded due to the low proportion of 
2759  this component in the drug product, and the low concentrations of lead in the other components. 
2760  Using these concentrations and the component percent composition (Table A.4.1), levels of 
2761  elemental impurities in the drug product can be determined using Equation 2 and compared to the 
2762  established PDE. The concentrations given in Table A.4.5 are only suitable for the component 
2763  proportions given in Table A.4.1. 
2764   
  84  Contains Nonbinding Recommendations 
 
2765  Table A.4.5: Example of Potential Concentrations of Elemental Impurities in the Components 
  Potential Concentration (g/g) 
Component 
Pb  As  Cd  Hg  Pd  V  Ni 
Drug Substance  <LoQ  5  <LoQ  <LoQ  500  <LoQ  750 
MCC  0.5  5  1  5  *  <LoQ  <LoQ 
Lactose  0.5  5  1  5  *  <LoQ  <LoQ 
Ca Phosphate  5  5  5  35  *  70  80 
Crospovidone  0.5  5  1  5  *  <LoQ  <LoQ 
Mg Stearate  5  10  5  125  *  <LoQ  100 
HPMC  2.5  5  1  5  *  <LoQ  <LoQ 
Titanium Dioxide  50  40  10  35  *  20  <LoQ 
Iron Oxide  50  100  50  200  *  5000  1200 
2766  * The risk assessment determined that Pd was not a potential elemental impurity; a quantitative 
2767  result was not obtained. 
2768   
2769  Option 3: Finished Product Analysis 
2770  For this example, consider the same solid oral drug product with a maximum daily intake of 2.5 
2771  grams, containing nine components (1 drug substance and eight excipients) used in Option 1, 2a 
2772  and 2b. The drug substance synthesis uses Pd and Ni catalysts, and Pb, As, Cd, Hg, and V are also 
2773  of concern on the basis of the risk assessment. The maximum concentration of each elemental 
2774  impurity in the drug product may be calculated using the daily intake of drug product and the 
2775  PDE of the elemental impurity using Equation 1. The total mass of each elemental impurity 
2776  should be not more than the PDE. 
2777   
2778  Table A.4.6: Calculation of Concentrations for the Finished Product 
  Maximum Permitted Concentration (g/g) 
  Daily                
Intake (g)  Pb  As  Cd  Hg  Pd  V  Ni 
Drug Product  2.5  2  6  2  12  40  40  80 
Maximum Daily Intake (g)  5  15  5  30  100  100  200 
2779   
2780  Illustrative Example  Elemental Impurities Assessment 
2781  The following example is intended as illustration of an elemental impurities risk assessment. 
2782  This example is intended for illustrative purposes and not as the only way to document the 
2783  assessment. There are many different ways to approach the risk assessment process and its 
2784  documentation. 
2785   
2786  This example relies on the oral drug product described in Appendix 4. Consider a solid oral drug 
2787  product with a maximum daily intake of 2.5 grams, containing nine components (1 drug substance 
2788  and eight excipients). The drug substance synthesis uses Pd and Ni catalysts. 
2789  The applicant conducts the risk assessment starting with the identification of potential elemental 
2790  impurities following the process described in Section 5. Because the applicant had limited 
2791  historical data for the excipients used in the drug product, the applicant determined that the Class 
  85  Contains Nonbinding Recommendations 
 
2792  1 elements (As, Cd, Hg, Pb) would be taken through the evaluation phase. The table below 
2793  shows a summary of the findings of the identification stage of the assessment. 
2794   
2795  Table A.4.7: Identification of Potential Elemental Impurities 
  Potential Elemental Impurities 
Component  Intentionally  Potential  Potential  Potential 
added  elemental  elemental  elemental 
impurities with a  impurities from  impurities from 
relatively high  manufacturing  container 
abundance  equipment  closure systems 
and/or 
are impurities in 
excipients 
Drug Substance  Pd, Ni  As  Ni  None 
MCC  None  As, Cd, Hg, Pb  None  None 
Lactose  None  As, Cd, Hg, Pb  None  None 
Ca Phosphate  None  As, Cd, Hg, Pb  V, Ni  None 
Crospovidone  None  As, Cd, Hg, Pb  None  None 
Mg stearate  None  As, Cd, Hg, Pb  Ni  None 
HPMC  None  As, Cd, Hg, Pb  None  None 
Titanium Dioxide  None  As, Cd, Hg, Pb  V  None 
Iron Oxide  None  As, Cd, Hg, Pb  V, Ni  None 
2796   
2797  The assessment identified seven potential elemental impurities requiring additional evaluation. 
2798  Three of the identified elements were found in multiple components. The applicant continued the 
2799  risk assessment by collecting information from vendors, published literature and data. The 
2800  individual component data in the risk assessment process is shown below in Table A.4.8. Total 
2801  daily masses of elemental impurities are calculated as the daily intake of the component times the 
2802  concentration. 
2803   
2804   
  86  Contains Nonbinding Recommendations 
 
2805  Table A.4.8: Elemental Impurity Assessment  Evaluation of Daily Contribution to the Total Mass of Elemental Impurities  
2806  in the Drug Product 
2807   
Daily  Measured Concentration (g/g)  Total Daily Mass of Elemental Impurity, g 
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 g  0.8 g  0.7 g  0.7 g 4 g  9.5 g  12.5 g 
2808  * The risk assessment determined that Pd was not a potential elemental impurity; a quantitative result was not obtained. 
2809   
2810  The next step in the risk assessment is to compare the measured or predicted levels in the drug product to the control threshold, using the  
2811  information in Table A.4.8, and determine appropriate actions. 
2812   
2813  Table A.4.9: Assessment Example  Data Entry Descriptions 
2814  Column 1:  Review the components of drug product for any elements intentionally added in the production (the primary source is 
2815  the drug substance). For those used, record the elements for further consideration in the assessment. 
2816  Column 2:  Identify any potential elements or impurities that are associated with excipients used in the preparation of the drug 
2817  product. Record the source(s) for further consideration in the assessment. 
2818  Column 3:  Identify any elemental impurities known or expected to be leached from the manufacturing equipment. Record the 
2819  specific elemental impurities for further consideration in the assessment. 
  87  Contains Nonbinding Recommendations 
 
2820  Column 4:  Identify any elemental impurities known or expected to be leached from the container closure system. Record the 
2821  specific elemental impurities for further consideration in the assessment. 
2822  Column 5:  Calculate the total contribution of the potential elemental impurity by summing the contributions across the 
2823  components of the drug product. 
2824  Column 6:  Assess the variability of the elemental impurity level(s) in the components 
2825  Column 7:  Enter the control threshold of each potential elemental impurity identified. If the variability is known and it is within 
2826  acceptable limits, the control threshold (30% of the PDE) for each elemental impurity can be applied. 
2827  Column 8:  Describe action taken  none if the value in column 5 is less than or equal to the control threshold (Column 7). Define 
2828  control element if material variability is high or control threshold is exceeded. 
2829   
  1  2  3  4  5  6  7  8 
    Leached from  Acceptable     
Intention- Elemental impurities  Total elemental 
  Manufacturing  container  variability of  Control   
ally added  with a relatively high  impurity 
Element  equipment  closure systems  elemental  threshold  Action 
(if used in  abundance and/or  contribution 
impurity 
the process)  are impurities in  g/ 
Contribution 
excipients 
As  No  Observed impurity in  No  No  0.8  Yes  4.5  no further controls 
all excipients and drug  required 
substance 
Cd  No  Observed impurity  No  No  0.7  Yes  1.5  no further controls 
in all excipients  required 
Hg  No  Observed impurity  No  No  0.7  Yes  9  no further controls 
in all excipients  required 
Pb  No  Observed impurity  No  No  1.2  Yes  1.5  no further controls 
in all excipients  required 
Pd  API  No  No  No  4.0  Yes  30  no further controls 
cata- required 
lyst 
Ni  API  Observed in 3  No  No  12.5  Yes  60  no further controls 
cata- excipients  required 
lyst 
  88  Contains Nonbinding Recommendations 
 
V  No  Observed in 3  No  No  9.5  Yes  30  no further controls 
excipients  required 
2830   
2831   
  89   
Contains Nonbinding Recommendations 
 
2832  Appendix 5:  Limits for Elemental Impurities by the Cutaneous and Transcutaneous 
2833  Route 
2834   
2835  TABLE OF CONTENTS 
2836   
2837  I.  BACKGROUND (1) ...................................................................................................... 91 
2838  II.  SCOPE (2) ...................................................................................................................... 92 
2839  III.  PRINCIPLES OF SAFETY ASSESSMENT FOR CUTEANEOUS PRODUCTS (3)
2840     ......................................................................................................................................... 92 
2841  A.  TRANSCUTANEOUS ABSORPTION OF ELEMENTAL IMPURITIES (E1) (3.1)
2842     ......................................................................................................................................... 92 
2843  B.  PDE FOR DRUG PRODUCTS DIRECTLY APPLIED TO THE DERMIS (3.2) . 93 
2844  IV.   ESTABLISHING THE CUTANEOUS PERMITTED DAILY EXPOSURE (PDE) 
2845  (4)..................................................................................................................................... 93 
2846  A.  ESTABLISHING THE CUTANEOUS MODIFYING FACTOR (CMF) (4.1) ....... 93 
2847  B.  CUTANEOUS PDE (4.2) .............................................................................................. 94 
2848  V.  CUTANEOUS CONCENTRATION LIMITS FOR NI AND CO (5) ...................... 95 
2849  VI.   PRODUCT RISK ASSESSMENT (6) ......................................................................... 95 
2850  VII.  CUTANEOUS PDE VALUES (7) ................................................................................ 96 
2851  VIII.  REFERENCES (8) ......................................................................................................... 98 
2852   
2853   
2854     
  90   
Contains Nonbinding Recommendations 
 
2855  I.  BACKGROUND (1) 
2856   
2857  In December 2014, ICH approved the ICH Q3D Guidance for Elemental Impurities developed 
2858  by the Expert Working Group. The Guidance provided Permitted Daily Exposures (PDEs) for 
2859  24 elemental impurities (EI) for the oral, parenteral, and inhalation routes of administration. In 
2860  section III.B (3.2) of the guidance, principles for establishing PDEs for other routes of 
2861  administration are described. During the course of the development of Q3D, interest was 
2862  expressed in developing PDEs for the cutaneous and transcutaneous route, as these products 
2863  remain the most significant area where PDEs for EI have not been formally established. 
2864  Appendix 5 is intended to expand upon the information given in the main text of the Q3D 
2865  Guidance and to provide more specific information regarding the cutaneous and 
2866  transcutaneous route of administration. 
2867  In establishing cutaneous and transcutaneous limits, the role of skin is paramount. The skin is 
2868  an environmental barrier and a complex organ that has many functions, including limiting the 
2869  penetration of exogenous materials, metabolism, prevention of water loss, temperature 
2870  regulation, and as an immune organ (Monteiro-Riviere and Filon, 2017). The skin is composed 
2871  of both an outer epidermis and an inner dermis, each composed of multiple cellular layers. 
2872  Dermal (or transcutaneous) absorption, i.e., the transport of a chemical from the outer surface 
2873  of the skin into systemic circulation, is dependent upon the properties of the skin, the 
2874  anatomical site, the nature of the chemical applied and the characteristics of the application. 
2875  The primary barrier to absorption is the outermost layer of the epidermis (i.e., the stratum 
2876  corneum) which typically consists of 15-20 layers of non-viable cells. The stratum corneum 
2877  (horny layer) serves as a highly effective barrier, especially to charged species, such as metal 
2878  ions. For this reason, transcutaneous delivery into the systemic circulation of materials 
2879  including any active pharmaceutical ingredient (API) typically requires physical and chemical 
2880  agents (e.g., penetration enhancers) to assist in the transcutaneous absorption of the API. 
2881  In respect to these penetration enhancers, it is noteworthy that agents that enhance 
2882  penetration of an API are usually not applicable for EI because of fundamental differences in 
2883  physico-chemical properties. Limited research has been conducted to evaluate the systemic 
2884  absorption of EIs applied to the skin. The skin may respond to exposure in various ways. For 
2885  example, approximately half of mercury vapor taken up by the skin (1 - 4% of the dose) was 
2886  shed by desquamation of epidermal cells for several weeks after exposure, while the remainder 
2887  in the skin was slowly released into general circulation (Hursh et al., 1989). Hostynek 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 Hostynek et al. (1993). This systemic 
2898  exposure is reported to be < 1% absorption for most of the evaluated EI in scope of this 
2899  guidance. Transcutaneous absorption of EI is discussed in more detail in section III (3). 
2900  Elements evaluated in this guidance were assessed by reviewing publicly available data 
2901  contained in scientific journals, government research reports and studies, and regulatory 
2902  authority research and assessment reports. In general, studies in the scientific literature simply 
  91   
Contains Nonbinding Recommendations 
 
2903  report disappearance of EI from the cutaneous layer rather than transcutaneous absorption. 
2904  Quantitative data are generally lacking for most EI and the associated counterion (Hostynek, 
2905  2003). Furthermore, there are no suitable standards for occupational exposure for the dermal 
2906  route for risk assessment. Consequently, a generic approach was adopted to establish limits as 
2907  opposed to an element-by-element basis. 
 
2908 
2909  II.  SCOPE (2)8 
2910  This Appendix to the Q3D Guidance applies to cutaneous and transcutaneous drug products 
2911  (referred to as cutaneous products throughout this Appendix) whether intended for local or 
2912  systemic effect. This Appendix does not apply to drug products intended for mucosal 
2913  administration (oral, nasal, vaginal), topical ophthalmic, rectal, or subcutaneous and subdermal 
2914  routes of administration. Products not covered by this Appendix should be evaluated in 
2915  accordance with the approach discussed in section III.B (3.2) of the main text of the Q3D 
2916  Guidance. 
2917   
2918  III.  PRINCIPLES OF SAFETY ASSESSMENT FOR CUTANEOUS PRODUCTS (3) 
2919   
2920  The literature review focuses on the forms likely to be present in pharmaceutical products (see 
2921  main guidance) and therefore the assessment relied on evaluating the available data for 
2922  inorganic forms of the EI and ranking the relevance of the data in the following order: human in 
2923  vivo data; animal in vivo data; in vitro data. 
2924   
2925  Local and systemic toxicities were considered. In general, there is no indication for local 
2926  toxicity on the skin, with the exception of sensitization. Review of systemic toxicity by the 
2927  dermal route, shows significant systemic toxicity for thallium. Since there is limited 
2928  information available on transcutaneous absorption of the elements addressed in this Addendum 
2929  it is not possible to address this percent absorption on an element-by-element basis and to allow 
2930  conversion of an existing PDE to the dermal route to support an element- by-element approach. 
2931  Therefore, a generic approach has been developed based on a systematic adjustment of the 
2932  parenteral PDE, which assumed 100% bioavailability, to derive a cutaneous PDE by using a 
2933  Cutaneous Modifying Factor (CMF) (see section IV (4)). The cutaneous PDE has been derived 
2934  for daily, chronic application to the skin. 
2935   
2936  A.  Transcutaneous Absorption of Elemental Impurities (EI) (3.1) 
2937  The extent of absorption into the systemic circulation (systemic absorption) is considered an 
2938  important component to the safety assessment of the elements. Review of studies of skin 
2939  penetration, absorption, systemic bioavailability and toxicity of the elements shows a lack of 
2940  data for many elements. For those elements that have been studied for transcutaneous 
2941  absorption and/or toxicity, the available data are rarely suitable for proper quantitative analysis 
2942  and the diverse experimental designs preclude inter-study or inter-element comparability 
2943  (Hostynek, 2003). The available data indicate that EIs are generally poorly absorbed through 
2944  intact skin even in the presence of enhancers. For example, absorption of Pb from lead oxide 
2945  under occlusion in rats was less than 0.005%, as measured by urinary Pb for 12 days following 
2946  exposure. Penetration of lead oxide was not detectable in an in vitro system with human skin 
2947  (ATSDR, 2019). 
 
8 The Q3D guidance is not intended to provide recommendations for labelling of allergens. Applicants should 
refer to regional guidance/recommendations or best practice for managing and labeling of allergens. 
 
  92   
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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 
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2996  section III.A (3.1), there are multiple factors that can influence this absorption. In lieu of 
2997  accounting for such factors individually, and in consideration of the relative lack of reliable 
2998  quantitative transcutaneous absorption data, an approach has been adopted for the derivation 
2999  of cutaneous PDEs, which is considered protective against potential systemic toxicities. To 
3000  account for these uncertainties, a CMF is generated using the approach outlined below. 
3001   
3002  1.  For EIs other than arsenic (As) and thallium (Tl), a maximum Cutaneous 
3003  Bioavailability (CBA) of 1% is used. 
3004   
3005  2.  To account for the various factors that can enhance CBA, a factor of 10 is applied to 
3006  increase the CBA (adjusted CBA). 
3007   
3008  3.  To calculate the CMF, the parenteral BA (100%) is divided by the adjusted CBA. 
 
3009 
3010  B.  Cutaneous PDE (4.2) 
3011  The Cutaneous PDE is calculated as 
3012  Cutaneous PDE = Parenteral PDE x CMF 
3013  Parenteral PDE calculations already include safety factors F1-F5 or are derived from Oral PDE, 
3014  which also include safety factors (see Appendix 1of ICH Q3D) to account for variability and 
3015  extrapolation. Therefore, no further adjustments are necessary for the cutaneous PDE. 
3016   
3017  The derived cutaneous PDEs are listed in Table A.5.1. 
3018   
3019  4.2.1  Derivation of PDE for EI, other than Arsenic (As) and Thallium (Tl) 
3020  For EI with low CBA (< 1%), a CMF of 10 is applied. 
3021   
3022  For EI with < 1% CBA, the adjusted CBA is 1% x 10 = 10% 
3023  Divide the parenteral BA by the adjusted CBA to derive the CMF 
3024  100%/10% = 10 
3025   
3026  The cutaneous PDE is derived as: 
3027  Cutaneous PDE = Parenteral PDE x CMF 
3028  Cutaneous PDE = Parenteral PDE x 10 
3029   
3030  See Table A.5.1 for cutaneous PDEs for individual EI. 
 
3031 
3032  4.2.2  Derivation of PDE for Arsenic 
3033  For inorganic arsenic, the available data indicate that the transcutaneous absorption is greater 
3034  than that observed for most other EI (approximately 5%) (ATSDR, 2016). Based on this, the 
3035  CMF for arsenic is 2, as shown in the calculation below 
3036   
3037  Derive the adjusted CBA: 5% x 10 = 50% 
3038  Divide parenteral BA by the adjusted CBA to derive the CMF 
3039  100%/50% = 2 
3040   
3041  The cutaneous PDE is derived as:  
3042  Cutaneous PDE = Parenteral PDE x CMF 
3043  Cutaneous PDE = 15 g/day x 2 = 30 g/day 
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3044 
3045  4.2.3  Derivation of PDE for Thallium 
3046  Thallium is highly absorbed through the skin. Since quantitative data are not available, it is 
3047  assumed to be effectively equivalent to parenteral levels. The adjusted PDE equals the 
3048  parenteral PDE, a CMF of 1 is used. 
3049   
3050  The cutaneous PDE is derived as: 
3051  Parenteral PDE = 8 g/day 
3052  Cutaneous PDE = 8 g/day x 1 = 8 g/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 g/cm2/week for Ni was originally established by Menne 
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; Ahlstrom 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 g/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 g/cm2/week  = 0.07 g/cm2/day 
3084  0.07 g/cm2/day x 250 cm2  = 17.5 g/day 
3085  17.5g/day / 0.5 g/day  = 35 g/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 
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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 (g/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 (g/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 (g/day) or cutaneous concentration (g/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 (g/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. 
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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 
(g/day)  (g/day)  (g/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  354  yes 
V  2A  100  10  1  100  -  yes 
Ni  2A  200  20  6  200  354  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 g/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 g/g which exceeds the CTCL of 35 g/g. In this situation, 
3153  the CTCL limit should be used. 
3154  5 Pd PDE will apply to iridium, osmium, rhodium, and ruthenium. 
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3155  Table A.5.2: Cutaneous PDE and Concentration Limits for a 10 g Dose 
    Cutaneous conc1  CTCL 
Element  Class  Cutaneous  for a 10 g daily  (g/g) 
PDE (g/day)  dose (g/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  202  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 g/g; based on a 1 g maximum daily dose of drug product, the calculated 
3160  cutaneous concentration is 50 g/g which exceeds the CTCL of 35 g/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  Ahlstrom MG, Thyssen JP, Wennervaldt M, Menne 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, Liden C, et al. Elicitation threshold of cobalt chloride: 
3181  analysis of patch test dose-response studies. Contact Dermatitis 2015; 74: 105-109. 
3182   
3183  Hostynek 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): 327345. 
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 Pattys 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: 444447. 
3197   
3198  Menne 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  SCCPs (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, Menne T, Spiewalk R, Vigan M, Gimenez-Arnau A, Liden 
3214  C. The EU Nickel Directive revisitedfuture 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.