EPA/635/R-19/149
IRIS Assessment Plan
www.epa.gov/iris
IRIS Assessment Plan for Inorganic Mercury Salts
(Scoping and Problem Formulation Materials)
(Mercuric Chloride [7487-94-7], Mercuric Sulfide [1344-48-5],
Mercurous Chloride [10112-91-1]]
October 2019
Integrated Risk Information System
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
-------
IRIS Assessment Plan for Inorganic Mercury Salts
DISCLAIMER
This document is a preliminary draft for review purposes only. This information is
distributed solely for the purpose of public comment. It has not been formally disseminated by
EPA. It does not represent and should not be construed to represent any Agency determination or
policy. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
ii DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
CONTENTS
AUTHORSI CONTRIBUTORS | REVIEWERS vi
1. INTRODUCTION 1
2. SCOPING AND INITIAL PROBLEM FORMULATION 3
2.1. BACKGROUND 3
2.2. SCOPING SUMMARY 5
2.3. PROBLEM FORMULATION 6
2.4. KEY SCIENCE ISSUES 11
3. OVERALL OBJECTIVE, SPECIFIC AIMS, AND DRAFT POPULATIONS, EXPOSURES,
COMPARATORS, AND OUTCOMES (PECO) CRITERIA 13
3.1. ASSESSMENT APPROACH 13
3.2. SPECIFIC AIMS 13
3.3. DRAFT POPULATIONS, EXPOSURES, COMPARATORS, AND OUTCOMES (PECO) CRITERIA 14
REFERENCES R-l
APPENDIX A. PHYSICAL AND CHEMICAL PROPERTIES OF INORGANIC MERCURY SALTS
(COMPARISON OF MERCURIC CHLORIDE, MERCUROUS CHLORIDE, AND MERCURIC SULFIDE) A-l
APPENDIX B. LITERATURE SEARCH STRATEGIES B-l
APPENDIX C. LITERATURE SEARCH METHODS AND INITIAL RESULTS C-l
APPENDIX D. INITIAL LITERATURE INVENTORY SUMMARIES D-l
This document is a draft for review purposes only and does not constitute Agency policy.
iii DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
TABLES
Table 1. Environmental Protection Agency (EPA) program and regional office interest in
an assessment of inorganic mercury salts 6
Table 2. Inorganic mercury salts oral values (mg/kg-day) from U.S. federal and state
agencies and international bodies 8
Table 3. Summary of mercuric chloride oral studies by evidence type, study design, and
health systems assessed 10
Table 4. Summary of mercuric sulfide oral studies by evidence type, study design, and
health systems assessed 11
Table 5. Draft populations, exposures, comparators, outcomes (PECO) criteria for the
inorganic mercury salts assessment 16
Table 6. Major categories of "Potentially Relevant Supplemental Material" 18
FIGURES
Figure 1. Integrated Risk Information System (IRIS) systematic review problem
formulation and method documents 2
Figure 2. Comparison of inorganic mercury salts oral reference values. Line segments
indicate relevant durations for individual reference values 8
This document is a draft for review purposes only and does not constitute Agency policy.
iv DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
ABBREVIATIONS
AD ME absorption, distribution, metabolism, and excretion
ATSDR Agency for Toxic Substances and Disease Registry
CA California
CASRN Chemical Abstracts Service registry number
CERCLA Comprehensive Environmental Response, Compensation, and Liability Act
CICAD Concise International Chemical Assessment Documents
DNT developmental neurotoxicity
DWEL drinking water equivalent level
EPA Environmental Protection Agency
EPCRA Emergency Planning and Community Right-to-Know Act
GI gastrointestinal
HA health advisory
HERO Health and Environmental Research Online
Hg mercury
HgCk mercuric chloride
Hg2Cb mercurous chloride
HgS mercuric sulfide
IAP IRIS Assessment Plan
IARC International Agency for Research on Cancer
IRIS Integrated Risk Information System
MCL maximum contaminant level
MEG-N military exposure guideline
MRL minimal risk level
NCEA National Center for Environmental Assessment
NOAEL no-observed-adverse-effect level
NTP National Toxicology Program
OLEM Office of Land and Emergency Management
ORD Office of Research and Development
OW Office of Water
PBPK physiologically based pharmacokinetic
PECO populations, exposures, comparators, and outcomes
PHG public health goals
RCRA Resource Conservation Recovery Act
REL reference exposure level
RfC inhalation reference concentration
RfD oral reference dose
RIVM Dutch National Institute for Public Health and the Environment
TDI tolerable daily intake
UF uncertainty factor
UFa interspecies uncertainty factor
UFh intraspecies uncertainty factor
WHO World Health Organization
WOS Web of Science
This document is a draft for review purposes only and does not constitute Agency policy.
v DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
AUTHORS | CONTRIBUTORS | REVIEWERS
Assessment Team
Nagu Keshava (Assessment Manager)
Amanda Persad
Suryanarayana Vulimiri
Systematic Review Support
Carolyn Gigot
Andrew Greenhalgh
Audrey Galizia
Krista Montgomery
Executive Direction
U.S. EPA/ORD/NCEA/Washington
U.S. EPA/ORD/NCEA/IRIS
U.S. EPA/ORD/NCEA/Washington
U.S. EPA/ORD/NCEA/IRIS
U.S. EPA/ORD/NCEA/IRIS
U.S. EPA/ORD/NCEA/IRIS
U.S. EPA/ORD/NCEA/IRIS
Tina Bahadori
Mary Ross
Emma Lavoie
Belinda Hawkins
Andrew Kraft
Kris Thayer
James Avery
David Bussard
Santhini Ramasamy
Contributors and Production Team
NCEA Center Director
NCEA Deputy Center Director
NCEA Assistant Center Director for Scientific Support
NCEA Associate Director for Health (acting)
NCEA/IRIS Associate Director for Science
NCEA/IRIS Division Director
NCEA/IRIS Deputy Director (acting)
NCEA/Division Director (Washington)
Branch Chief, EICG branch
Hillary Hollinger
Ryan Jones
Vicki Soto
Dahnish Shams
Maureen Johnson
HERO Librarian
HERO Director
Project Management Team
Project Management Team
NCEA Webmaster
This document is a draft for review purposes only and does not constitute Agency policy.
vi DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
//?/S Assessment Plan for Inorganic Mercury Salts
1. INTRODUCTION
The Integrated Risk Information System (IRIS) Program is undertaking a [re]assessment of
the health effects of inorganic mercury salts (mercuric chloride, mercuric sulfide, mercurous
chloride). Among these three salts, only one, mercuric chloride, has a previously developed IRIS
reference dose (RfD)
[https://cfpub.epa.gov/ncea/iris2/chemicalT,anding.cfm?substance_nmbr=692 (U.S. EPA. 1995)].
During fiscal year 2018, Environmental Protection Agency (EPA) prioritized its IRIS assessments to
meet the highest needs of EPA programs and regions and to bring greater focus to assessments
under development further described in the December 2018 IRIS Program Outlook
(https://www.epa.gov/sites/production/files/2018-
12/documents/iris_program_outlook_december_2018.pdf). IRIS assessments provide high-quality,
publicly available information on the toxicity of chemicals to which the public might be exposed.
These assessments are not regulations but provide a critical part of the scientific foundation for
decisions made in EPA program and regional offices to protect public health.
As part of the assessment development, the IRIS Program undertakes scoping and problem
formulation activities. During scoping activities, the IRIS Program consults with EPA program and
regional offices to identify the nature of the hazard characterization needed, the most important
exposure pathways, and the level of detail required to inform Agency decisions. A broad,
preliminary literature survey and summary of the underlying data may also be conducted to help
identify the extent of the evidence and health effects that have been studied for the chemical of
interest. Based on the scope defined by EPA, the IRIS Program undertakes problem formulation
activities to frame the scientific questions that will be the focus of the assessment. A summary of
the IRIS Program's scoping and problem formulation efforts and conclusions are contained in the
IRIS Assessment Plan (IAP).
The IAP is followed by development of a Systematic Review Protocol, which presents
detailed methods for conducting the full systematic review and dose-response analysis, including
any adjustments made to the IAP in response to public input. The IAP describes what will be
assessed, and the chemical-specific protocol describes how the assessment will be conducted.
Figure 1 displays the context of the IAP and Systematic Review Protocol in the systematic
review process.
This document presents the draft IAP for oral exposures of the three most commonly
occuring inorganic mercury salts—mercuric chloride, mercuric sulfide, and mercurous chloride—
deemed important to EPA's program offices. It describes the Agency's need for the assessment;
objectives and specific aims of the assessment; draft populations, exposures, comparators, and
outcomes (PECO) criteria that outline the evidence considered most pertinent to address the
This document is a draft for review purposes only and does not constitute Agency policy.
1 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
specific aims of the assessment; and identification of key areas of scientific complexity. Brief
background information on uses and the potential for human exposure to inorganic mercury salts is
provided for context.
Systematic
Review Protocol
Literature
Inventory
Study
Evaluation
Data
Extraction
Evidence
Integration
Derive Toxicity
Values
t\ /T\ ¦
Initial ProWen
Formulation
—s—5—i—i—i—^
Literature preirtinary organize Evidence Analysis select artd Model 1 /
search Analysis plan Hazard Review and synthesis StiNjies \/
Assessment
Plans:
What the
w
Protocols: How the assessment will be conducted (specific
assessment
procedures and approaches for each assessment component, with
will cover
rationale where needed)
Assessment
Developed
Figure 1. Integrated Risk Information System (IRIS) systematic review
problem formulation and method documents.
This document is a draft for review purposes only and does not constitute Agency policy.
2 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
//?/S Assessment Plan for Inorganic Mercury Salts
2.SCOPING AND INITIAL PROBLEM FORMULATION
2.1. BACKGROUND
Mercury occurs naturally in the environment and can exist as elemental, organic, or
inorganic mercury. This IRIS assessment will evaluate the potential human health effects of the
three most commonly occurring inorganic mercury salts: mercuric chloride (HgCk), mercuric
sulfide (HgS, cinnabar), and mercurous chloride (Hg2Ck, calomel) (WHO. 2003). Elemental mercury
and methylmercuiy are not included in this assessment EPA is currently evaluating the
developmental neurotoxicity (DNT) effects following methylmercury exposure in humans to update
the oral RfD. There are no ongoing efforts to update the inhalation reference concentration (RfC)
for elemental mercury based on prioritization efforts described in the December 2018 IRIS
Program Outlook. Further details on the elemental and methylmercury assessments can be found
at https://cfpub.epa.gov/ncea/iris2/chemicall,anding.cfm?substance_nmbr=370 and
https://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm7deick343693. respectively.
Mercury occurs naturally in geologic materials in the environment and can exist in
inorganic form as salts. It also can exist in elemental form as a liquid or gas or in its highly toxic
organic form (methylmercuiy). In its inorganic form, mercury occurs abundantly in the
environment, primarily as the minerals cinnabar (HgS) and metacinnabar and as impurities in
other minerals (IJSGS. 1970). Its geologic associations are with volcanic rocks and hydrothermal
systems, where it can readily combine with chlorine, sulfur, and other elements and subsequently
weather to form inorganic salts.
Inorganic mercury salts can be transported in water and occur in soil. Dust containing
these salts can enter the air from mining deposits of ores that contain mercury. Emissions of both
elemental or inorganic mercury can occur from coal-fired power plants, burning of municipal and
medical waste, and from factories that use mercury. Inorganic mercury can also enter water or soil
from the weathering of rocks that contain inorganic mercury salts, and from factories or water
treatment facilities that release water contaminated with mercury (ATSDR 1999).
Although the use of mercury salts in consumer products, such as medicinal products, are
phased out, inorganic mercury compounds are still being widely used in skin lightening soaps and
creams. Mercuric chloride is used in photography and as a topical antiseptic and disinfectant, wood
preservative, and fungicide. In the past, mercurous chloride was widely used in medicinal products,
including laxatives, worming medications, and teething powders. It has since been replaced by safer
and more effective agents (ATSDR 1999). Mercuric sulfide is used to color paints and is one of the
red coloring agents used in tattoo dyes (ATSDR 1999). Details of the physical and chemical
properties of each of the compounds is provided in Supplemental Material, Appendix A, Table A-l.
This document is a draft for review purposes only and does not constitute Agency policy.
3 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
//?/S Assessment Plan for Inorganic Mercury Salts
Human exposure to inorganic mercury salts can occur both in occupational and
environmental settings (ATSDR, 1999). Occupations with higher risk of exposure to mercury and
its salts include mining, electrical equipment manufacturing, and chemical and metal processing in
which mercury is used. In the general population, exposure to mercuric chloride can occur through
the dermal route from the use of soaps and creams or topical antiseptics and disinfectants
(Mckelvey et al., 2011). Another, less well-documented, source of exposure to inorganic mercury
salts among the general population is from their use in ethnic religious, magical, and ritualistic
practices and in herbal remedies (WHO, 2003).
Although inorganic mercury salts can enter the body through ingestion, inhalation, or
through the dermal exposure route, there is limited scientific data on both the inhalation and
dermal routes of exposure (ATSDR. 1999). Oral exposures have been well studied based on the
understanding that ingestion is the primary route through which most inorganic mercury salts are
absorbed in the body. When inorganic mercury salts are ingested, up to 40% can enter through the
stomach and intestines; however, less than 10% is generally absorbed through the intestinal tract
(ATSDR. 1999). The extent of transport across the intestinal tract depends on the compound's
solubility (Fribergand Nordberg. 1973) and how easily it dissociates in the intestinal lumen to
become available for absorption (Endo etal., 1990). Absorption of mercurous formsi is less likely
than absorption of mercuric forms due to the former's poor solubility (Friherg and Nordberg,
1973). In animal studies, using whole-body retention data to indicate absorption, it is estimated
that 20-25% absorption occurs when mercuric chloride is given via the oral route of exposure
(Nielsen and Andersen. 1990). This oral absorption has been shown to vary depending on the
intestinal pH (Fndo etal., 1990), age, and diet (Kostial etal., 1978). Nutritional status might also
contribute to the intestinal absorption of Hg2+ because of competition with nutritionally essential
divalent cations such as Cu2+ or Zn2+ for membrane-embedded transporters. Although mercurous
chloride is insoluble and not readily absorbed, small amounts may be converted into the mercuric
ion and then absorbed in the lumen of the intestine, causing the toxicity. Evidence of dermal
absorption in individuals following dermal application of ointments that contained inorganic
mercury salts (Kang-Yum and Oransky, 1992; Bourgeois etal., 1986; De Bontetal., 1986) and in
urine samples from women using skin lightening creams containing inorganic mercury salts
(Mckelvey etal,. 2011: Barr etal,. 1973) have been reported. Although small amounts of inorganic
mercury salts can enter through skin (WHO. 2003). inhalation and dermal penetration are generally
not considered to be significant routes of exposure for inorganic mercury salts because of their
physical and chemical properties.
1Mercury with a valence state of +1 is referred to as mercurous mercury (e.g., mercurous chloride), and
mercury with a valence state of +2 is referred to as mercuric mercury (e.g., mercuric chloride, mercuric
sulfide). Once absorbed into the system, inorganic mercury enters an oxidation-reduction cycle. Absorbed
divalent cations from exposure to mercuric compounds can, in turn, be reduced to the metallic or
monovalent form and released as exhaled metallic mercury vapor fATSDR, 1999],
This document is a draft for review purposes only and does not constitute Agency policy.
4 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
//?/S Assessment Plan for Inorganic Mercury Salts
Once absorbed into the body, inorganic mercury salts are systemically distributed and
readily accumulate in the kidneys and liver (Nielsen and Andersen, 1QQf); Yeoh etal., 1989). For
instance, Sin etal. (1983) found the kidney to have the highest mercury levels following repeated
oral exposure of mice to mercury chloride over a period of 2-8 weeks. The amount of inorganic
divalent mercury that crosses the blood-brain and placental barriers is very low because of its poor
solubility (Inouye and Kajiwara, 1 QQf); Clarkson, 1989). However, occasionally some
methylmercury can be converted to inorganic mercury in the brain, and if this happens, it can
remain in the brain for a long time (ATSDR, 1999). Inorganic mercury salts are mainly excreted
through urine or feces over a period of several weeks or months (ATSDR. 1999). The elimination
half-life for inorganic salts is about 40 days (Goyer. 1991). Other minor routes of excretion from
the human body include exhalation through the lungs and by secretion in saliva, bile, and sweat
(Clarkson etal., 1988).
An assessment for mercuric chloride is currently available on the IRIS Program website
[https://cfpub.epa.gov/ncea/iris2/chemicalT,anding.cfm?substance_nmbr=692 (U.S. EPA. 1995)].
In 1995, IRIS derived an oral RfD value of 3 x 10-4 mg/kg-day for mercuric chloride based on
autoimmune effects (autoimmune glomerulonephritis) in brown Norway rats in
subchronic-duration feeding and subcutaneous studies (Andres, 1984; Bernaudin etal., 1981; Druet
etal., 1978). An RfD for mercuric sulfide or mercurous chloride is not available on IRIS at this time.
No inhalation toxicity values (RfC) have been derived for any of the inorganic mercury salts
(mercuric chloride, mercuric sulfide, or mercurous chloride). A cancer assessment for mercuric
chloride was conducted by EPA in 1995. Based on the qualitative weight-of-evidence
characterization, mercuric chloride was classified as a possible human carcinogen. However, no
quantitative cancer values were derived for either oral or inhalation exposures because of lack of
human data and limited animal carcinogenicity data.
[https://cfpub.epa.gov/ncea/iris2/chemicalT,anding.cfm?substance_nmbr=692 (U.S. EPA. 1995)].
2.2. SCOPING SUMMARY
During scoping, the IRIS Program met with EPA program and regional offices that had
interest in an IRIS assessment for inorganic mercury salts to discuss specific assessment needs.
Table 1 provides a summary of input from this outreach.
This document is a draft for review purposes only and does not constitute Agency policy.
5 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
//?/S Assessment Plan for Inorganic Mercury Salts
Table 1. Environmental Protection Agency (EPA) program and regional office
interest in an assessment of inorganic mercury salts
EPA program or
regional office
Oral
Inhalation
Statutes/regulations
Anticipated uses/interest
OLEM
V
•/*
CERCLA; EPCRA; RCRA
Subtitle 1 (underground
storage tanks)
Toxicological information from inorganic
mercury salts may be used to make risk
determinations for response actions
(e.g., short-term removals, long-term
remedial response actions) under CERCLA
and RCRA including Subtitle 1. For example,
CERCLA authorizes EPA to conduct short- or
long-term cleanups at Superfund sites and
later recover cleanup costs from potentially
responsible parties under Section 107.
CERCLA = Comprehensive Environmental Response, Compensation, and Liability Act; EPCRA = Emergency
Planning and Community Right-to-Know Act; OLEM = Office of Land and Emergency Management;
RCRA = Resource Conservation Recovery Act.
Additional discussions with OLEM indicated a primary need for oral exposure values and no anticipated need for
inhalation values. In addition, dermal exposure was not indicated as a need.
2.3. PROBLEM FORMULATION
EPA has identified the Agency for Toxic Substances and Disease Registiy (ATSDR)
Toxicological Profile for Mercury (ATSDR. 1999} as the most recent health agency assessment to
help identify the health effects most likely to require critical evaluation, although all potential
health effects will be considered in this assessment. The ATSDR toxicological profile includes
information on different forms of mercury including metallic mercury (also known as elemental
mercury), inorganic mercury, and organic mercury. However, this assessment will focus on three
inorganic mercury salts (i.e., mercuric chloride, mercurous chloride, and mercuric sulfide) and only
for the oral route of exposure. Figure 2 provides an overview of current (July 2019) oral values and
standards (including toxicity values, health advisories, and regulations) from different state and
federal agencies and international bodies for inorganic mercury salts, while Table 2 specifically
provides the endpoints and the basis for derivation of the oral toxicity values from federal and
international bodies. Unlike the toxicity values presented in Table 2, it must be noted that not all of
the information presented in the Figure 2 is directly comparable. Specifically, in addition to toxicity
values that may inform regulatory decisions, Figure 2 also provides dose levels (mg/kg/day) and
exposure concentrations (mg/L) that are based on toxicity values (or similar estimates) combined
with other information and considerations (e.g., human exposure information). These other values
and standards include non-enforceable public health goals (e.g., EPA HA, WHO guideline, Cal EPA
PHG) as well as an EPA MCL, which is enforceable. ATSDR (1999) has derived oral minimal risk
levels (MRLs) for acute (0.007 mg/kg-day) and intermediate (0.002 mg/kg-day) durations of
This document is a draft for review purposes only and does not constitute Agency policy.
6 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
IRIS Assessment Plan for Inorganic Mercury Salts
exposure to individual inorganic mercury salts based on kidney effects reported in a 1993 National
Toxicology Program (NTP) study of mercuric chloride (NTP. 1993}. Most of the supporting studies
of oral exposure to inorganic mercury salts were on mercuric chloride. The findings reported in
ATSDR (1999) are consistent with other assessments (WHO, 2003: U.S. EPA. 1995). The World
Health Organization (WHO) derived a toxicity value of 0.002 mg/kg-day based on renal effects in
rats (WHO, 2003). EPA-IRIS derived an oral RfD in 1995 for mercuric chloride based on
autoimmune effects (autoimmune glomerulonephritis) of 3 x 10-4 mg/kg-day. EPA (Office of
Water) derived a chronic maximum contaminant level (MCL) value of 0.002 mg/L for mercury salts
using drinking water equivalent level (DWEL) values based on autoimmune glomerulonephritis in
rats (U.S. EPA. 2018.1988). The International Agency for Research (IARC) concluded that there is
limited evidence in experimental animals for the carcinogenicity for mercuric chloride and it is not
classifiable as to its carcinogenicity to humans (Group 3) (IARC, 1993).
Acute
Intermediate I Longer-Term
Chronic / Lifetime
MEG-N, HgCl2 O
ATSDR-MRL
*
MEG-N, HgS O
¦X
~
EPA/OW HA
ATSDR-MRL
* -X
EPA/OW DWEL Q]
1
WHO Guideline 0
EPA/OW HA
EPA/OW MCL
Cal EPA PHG -0
RIVMTDI 0
EPA/IRIS RfD, HgCI (0
I
CA-REL K
1
10 100 1,000
Duration (Days)
10,000
100,000
X ATSDR-MRL
~ EPA/IRIS RfD £
8
cc
$
* RIVM TDI Q
X CA-REL
O MEG-N
~ Cal EPA PHG
c
DO EPA/OW DWEL ~
flj
c
a
~ EPA/OW MCI c
O
O
Q EPA/OW HA
~ WHO Guideline
ATSDR = Agency for Toxic substances and Disease Registry; CalEPA = California Environmental Protection Agency;
DWEL = Drinking Water Equivalent Level; EPA = Environmental Protection Agency; HA = health advisory; IRIS =
Integrated Risk Information System; MCL = Maximum Contaminant Level; MEG-N = Military Exposure Guideline;
MRL = Minimal Risk Level; OW = Office of Water; PHG = public health goals; REL = reference exposure level; RfD =
Reference Dose; RIVM = Dutch National Institute for Public Health and the Environment; TDI = tolerable daily
intake; WHO = World Health Organization,
This document is a draft for review purposes only and does not constitute Agency policy,
7 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
IRIS Assessment Plan for Inorganic Mercury Salts
Figure 2. Current oral values and standards for inorganic mercury salts. Line
segments indicate relevant durations for individual values.
Table 2. Inorganic mercury salts oral toxicity values (mg/kg-day) from U.S.
federal and international bodies
Reference
Value
(mg/kg-d)
Exposure
duration
Chemical note
Endpoints/basis
U.S. EPA
(1995)
3 x 10"4
Chronic
Mercuric chloride
Autoimmune effects (autoimmune
glomerulonephritis) UF = 1,000 (10
for LOAEL to NOAEL, 10 for
subchronic studies and a combined
10 for both UFfl and UFH) (U.S. EPA,
1987; Andres, 1984; Bernaudin et al.,
1981: Druet etal.. 1978)
ATSDR (1999)
2 x 10"3
Intermediate
Mercurous chloride,
mercuric chloride,
mercuric sulfide, and
mercuric acetate
Kidney-weight changes in rats
UF= 100 (UFA = 10, UFh = 10),
following 26 weeks oral exposure to
mercuric chloride (NTP, 1993)
WHO (2003)
2 x 10"3
Chronic
Mercuric chloride
Renal effects in rats
UF = 100 (UFa = 10, UFh = 10) (NTP,
1993)
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level;
UF = uncertainty factor; UFA = interspecies uncertainty factor; UFH = intraspecies uncertainty factor.
In this IAP, systematic review methods were used to identify initial literature for all three
inorganic mercury salts. These methods were implemented in accordance with the IRIS Quality
Assurance Project Plan. The literature search focused on studies published after the release of the
ATSDR Toxicological Profile in 1999. Searches included studies from 1997 through February 2019
to overlap at least 2 years to ensure no studies were missed. PubMed, Toxline, and Web of Science
(WOS) databases were searched. A PECO (see Table 5) was used to focus the research question(s),
search terms, and inclusion/exclusion criteria in the evidence map. Detailed literature search
strategies (see Appendix B), literature search methods and initial results (see Appendix C), and
initial literature inventory summaries (see Appendix D, Figure D-l to Figure D-6) are described in
the supplemental materials/appendices at the end of this document The results obtained from the
systematic review process for both oral and inhalation studies, helped inform the specific aims and
anticipated analysis.
Abstracts and full text were screened for oral studies (see Figure D-l to Figure D-3) for all
three inorganic mercury salts. Studies that did not meet the PECO criteria were either excluded or
tagged as supplemental material. Mercuric chloride had 131 (2 human and 129 animal) studies
This document is a draft for review purposes only and does not constitute Agency policy.
8 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
//?/S Assessment Plan for Inorganic Mercury Salts
that warranted further evaluation. Over 700 studies (mechanistic and absorption, distribution,
metabolism, and excretion (ADME) studies) were tagged as supplemental. Similarly, 30 animal
studies were considered for further evaluation for mercuric sulfide. Table 3 and Table 4 provide
the summaries of mercuric chloride and mercuric sulfide oral studies, respectively, organized by
evidence type, study design, and health systems assessed. No oral studies met the PECO criteria for
mercurous chloride.
Similarly, abstract and full-text screening was conducted for inhalation studies (see Figure
D-4 to Figure D-6) for all three inorganic mercury salts. One epidemiology study that was identified
for mercuric chloride will be further evaluated for its suitability in the assessment. No inhalation
studies were identified during literature screening for mercuric sulfide and mercurous chloride.
Therefore, this assessment will focus on deriving reference values for oral exposures based on the
following considerations: (1) the failure to identify inhalation studies after abstract and full-text
level screening for any of the three inorganic mercury salts, and (2) further discussion and
clarification from the interested EPA office that exposure to inorganic mercuiy salts via inhalation
is unlikely, it was determined this assessment will focus on the oral route of exposure.
This document is a draft for review purposes only and does not constitute Agency policy.
9 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Table 3. Summary of mercuric chloride oral studies by evidence type, study
design, and health systems assessed
Health outcome
Animal
Human
Mouse
Rat
General/
occupation
Subchronic
Chronic
Repro/
dev
Subchronic
Chronic
Repro/
dev
ADME/PBPK
8
2
1
12
1
3
Cancer
0
0
0
1
0
0
Cardiovascular
1
0
0
4
1
1
Developmental
0
0
1
1
0
1
Endocrine
2
1
1
7
1
0
Gastrointestinal
1
0
0
3
0
2
Hematologic
0
1
0
6
1
0
Hepatic
4
0
0
6
1
2
Immune
4
0
2
3
0
1
2
Lymphatic
0
0
0
0
0
1
Nervous
2
1
2
11
1
4
Other
4
1
1
12
3
4
Renal
5
1
0
9
2
2
Reproductive
5
1
1
8
1
1
Respiratory
0
0
0
2
0
0
Systemic/whole body
10
1
2
18
3
5
Urinary
1
0
0
2
1
1
PBPK = physiologically based pharmacokinetic.
This document is a draft for review purposes only and does not constitute Agency policy.
10 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Table 4. Summary of mercuric sulfide oral studies by evidence type, study
design, and health systems assessed
Animal
Health outcome
Mouse
Rat
Subchronic
Repro/dev
Subchronic
ADME/PBPK
3
1
1
Cardiovascular
0
0
0
Developmental
0
1
0
Hematologic
1
1
0
Hepatic
2
0
0
Nervous
2
1
0
Renal
1
0
1
Systemic/whole body
0
1
1
PBPK = physiologically based pharmacokinetic.
1 Based on a preliminary literature survey, EPA anticipates conducting a further systematic
2 review analysis for the following health effect categories based on the available data and sensitivity
3 of the endpoints:
4 • Renal effects
5 • Immunological effects
6 • Nervous system effects
7 • Hepatic effects
8 • Reproductive effects
9 • Hematologic effects
2.4. KEY SCIENCE ISSUES
10 Based on the preliminary literature survey the following key scientific issues and potential
11 mode-of-action hypotheses were identified that warrant evaluation in this assessment.
This document is a draft for review purposes only and does not constitute Agency policy.
11 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
//?/S Assessment Plan for Inorganic Mercury Salts
• Key science issue #1: Consideration of the use of mercuric chloride information to
inform the assessment of mercuric sulfide: The systematic review efforts identified
30 animal oral studies for further study evaluation for determining suitable health
outcomes for mercuric sulfide. Depending on the quality of the available evidence, relevant
studies will be considered for deriving the toxicity reference value using traditional
dose-response assessment methods. If this is not possible, alternative methods will be
considered. These alternative methods may include the consideration of using mercuric
chloride information to assess potential mercuric sulfide human health hazards. Both
mercuric chloride and mercuric sulfide are divalent and have mercury in +2 oxidation state;
however, the solubilities of the two salts differ by about four orders of magnitude. Thus, the
bioavailability for mercuric sulfide is expected to be low compared with mercuric chloride.
Therefore, an understanding of the toxicokinetic and toxicodynamic profiles of mercuric
chloride versus those of mercuric sulfide will be informative in determining the human
health hazards of these salts.
• Key science issue #2: Consideration of the use of mercuric chloride information to
inform the assessment of mercurous chloride: The systematic review did not identify
any animal or human studies for further study evaluation for any health outcomes for
mercurous chloride. In the absence of data, alternative methods to assess the human health
hazard of this chemical may be considered. These alternative methods may include the
consideration of using mercuric chloride information to assess potential mercurous
chloride human health hazards. These compounds have different oxidation states
(mercuric chloride as Hg2+ and mercurous chloride as Hgi+) and their solubilities differ
significantly (the mercurous form is less soluble and, presumably, less bioavailable).
Therefore, an understanding of the toxicokinetic and toxicodynamic profiles of mercuric
chloride versus those of mercurous chloride will be informative in determining the human
health hazards of these salts.
This document is a draft for review purposes only and does not constitute Agency policy.
12 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
3.OVERALL OBJECTIVE, SPECIFIC AIMS, AND DRAFT
POPULATIONS, EXPOSURES, COMPARATORS,
AND OUTCOMES (PECO) CRITERIA
1 The overall objective of this assessment is to identify adverse health effects and
2 characterize exposure-response relationships for these effects of inorganic mercury salts
3 (i.e., mercuric chloride, mercuric sulfide, and mercurous chloride). This assessment will use
4 systematic review methods to evaluate the epidemiological and toxicological literature for
5 inorganic mercury salts, including consideration of relevant mechanistic evidence. The evaluation
6 and analyses conducted in this assessment will be consistent with relevant EPA guidance.2 The
7 systematic review protocol will be disseminated after release of the draft assessment plan and will
8 reflect changes made to the specific aims and PECO in response to public input.
3.1. ASSESSMENT APPROACH
9 A standard approach will be followed to derive toxicity values (RfDs) for these inorganic
10 mercury salts, as appropriate based on the available evidence. When available evidence is lacking,
11 alternative methods, including the potential use of toxicokinetic and/or toxicodynamic information
12 for one salt to inform the assessment of another salt, will be considered to characterize the human
13 health hazards of these salts.
3.2. SPECIFIC AIMS
14 For each of the three inorganic mercury salts, the assessment will:
15 • Prepare an initial literature inventory to identify epidemiology and toxicology studies
16 reporting the effects of exposure to inorganic mercury salts as outlined in the PECO (see
17 Section 3.3). Literature dated from 1997 onwards will be considered for evaluation. Foi-
ls information published prior to 1997, the ATSDR document, that undergoes rigorous
19 interagency review and public comment, (ATSDR. 1999) will be used as a resource. In
20 addition, studies cited in the Health Effects chapter of the ATSDR assessment will be
21 screened against the PECO and all studies that meet the PECO criteria will be subject to
22 subsequent systematic review steps, including study evaluation and considered as part of
23 evidence integration and suitability for dose-response analysis. Furthermore, studies
24 containing supplemental material that may be potentially relevant to an assessment will be
25 tracked during the literature screening process. Supplemental material includes
26 mechanistic evidence informative for the mode of action/adverse outcome pathway
2EPA guidance documents: http://www.epa.gov/iris/basic-information-about-integrated-risk-information-
system#guidance/.
This document is a draft for review purposes only and does not constitute Agency policy.
13 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
1 analysis, ADME information, sensitization studies etc. (See table 6 for a full listing of types of
2 supplemental material).
3 • Determine the extent to which a mechanistic analysis is warranted, based on factors such as
4 scope, complexity, and confidence in the evidence in humans and animals, likelihood to
5 impact evidence synthesis conclusions for human health, and directness or relevance of the
6 model systems for understanding potential human health hazards.
7 • Conduct study quality evaluations (risk of bias and sensitivity) using validated criteria for
8 individual epidemiology and toxicological studies and physiologically based
9 pharmacokinetic (PBPK) models, if the data are available.
10 • Extract data on relevant health outcomes from epidemiological and toxicological studies.
11 • Synthesize the evidence across studies, assessing similar health outcomes using a narrative
12 approach.
13 • For each health outcome, express strength of evidence conclusions from across studies (or
14 subsets of studies) separately for studies in humans and animals, respectively. If studies
15 informing mechanisms were synthesized, then mechanistic evidence from either human or
16 animal studies will be integrated with the health effects evidence; will also consider life
17 stage-specific differences in susceptibility, where data are available.
18 • For each health outcome under consideration for the derivation of toxicity values of
19 inorganic mercury salts, integrate the strength of evidence conclusions across evidence
20 streams (human and animal) to conclude whether a substance is hazardous to humans;
21 identify and discuss issues concerning potentially susceptible populations and life stages.
22 • Derive toxicity values as supported by the available data.
23 • Characterize uncertainties and identify key data gaps and research needs, such as
24 limitations of the evidence base, limitations of the systematic review, and consideration of
25 dose relevance and pharmacokinetic differences when extrapolating findings from higher
26 dose animal studies to lower levels of human exposure.
3.3. DRAFT POPULATIONS, EXPOSURES, COMPARATORS, AND
OUTCOMES (PECO) CRITERIA
27 The PECO is used to identify the evidence that addresses the specific aims of the
28 assessment, as well as to focus the search terms and inclusion/exclusion criteria in a systematic
29 review. The draft PECO for inorganic mercury salts (see Table 5) was based on (1) nomination of
30 the chemicals for assessment, (2) discussions with scientists in EPA program and regional offices to
31 determine the scope of the assessment that will best meet Agency needs, and (3) preliminary
32 review of the health effects literature for inorganic mercury salts (primarily reviews and
33 authoritative health assessment documents such as ATSDR and systematic review of literature) to
This document is a draft for review purposes only and does not constitute Agency policy.
14 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
identify the major health hazards associated with exposure to inorganic mercuiy salts and key
areas of scientific complexity.
This document is a draft for review purposes only and does not constitute Agency policy.
15 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Table 5. Draft populations, exposures, comparators, outcomes (PECO) criteria
for the inorganic mercury salts assessment
PECO element
Evidence
Populations
Human: Anv population and life stage (occupational or general population, including
children and other sensitive populations).
Animal: Nonhuman mammalian animal species (whole organism) of anv life stage
(including preconception, in utero, lactation, peripubertal, and adult stages).
Nonmammalian models and in vitro studies will be tracked as supplemental.
Exposures
Exposure based on administered dose or concentration, biomonitoring data
(e.g., urine, blood, or other specimens), environmental or occupational-setting
measures (e.g., air, water levels), or job title or residence. Relevant forms are listed
below:
• Mercuric chloride (7487-94-7) and all synonyms including mercuric
perchloride, mercury bichloride, mercury chloromercurate (II), mercury
dichloride, mercury perchloride, mercury (II) chloride, HgCI2,
dichloromercury, calochlor, bichloride of mercury
• Mercuric sulfide (1344-48-5) and synonyms including cinnabar, mercury (II)
sulfide, mercury (II) sulfide black, mercury (II) sulfide red, mercury sulfide,
mercury sulphide, vermilion, Chinese red, ethiops mineral, HgS
• Mercurous chloride (10112-91-1) and synonyms including calomel,
calogreen, chloromercury, dimercury dichloride, mercury (1) chloride,
mercury chloride, mercury monochloride, mercury protochloride, mercury
subchloride, mild mercury chloride, Hg2CI2
Human: Anv exposure to the relevant forms of inorganic mercurv salts listed above,
including occupational exposures via oral or inhalation route. Other exposure
routes, including dermal exposure, will be tracked during screening as "potentially
relevant supplemental information."
Animal: Anv exposure to inorganic mercurv salts via the oral or inhalation route.
Studies involving exposures to mixtures will be included only if they include exposure
to inorganic mercury salts alone. Other exposure routes, including dermal or
injection exposures, will be tracked during screening as "potentially relevant
supplemental information."
Comparators
Human: A comparison or referent population exposed to lower levels (or no
exposure/exposure below detection limits) of inorganic mercury salts, or exposure to
inorganic mercury salts for shorter periods of time. Case reports and case series will
be tracked as "potentially relevant supplemental information."
Animal: A concurrent control group exposed to vehicle-onlv treatment or untreated
control.
This document is a draft for review purposes only and does not constitute Agency policy.
16 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
//?/S Assessment Plan for Inorganic Mercury Salts
Table 5. Draft populations, exposures, comparators, outcomes (PECO) criteria
for the inorganic mercury salts assessment (continued)
PECO element
Evidence
Outcomes
All health outcomes (both cancer and noncancer). In general, endpoints related to
clinical diagnostic criteria, disease outcomes, histopathological examination, or other
apical/phenotypic outcomes will be prioritized for evidence synthesis over outcomes
such as biochemical measures. As discussed above, based on preliminary screening
work, EPA anticipates that a systematic review for health effect categories other
than those identified (i.e., renal, immunological, neurological, hepatic,
hematological, and reproductive effects) will not be undertaken unless a significant
amount of new evidence is found upon review of references during the
comprehensive literature search.
PBPK models
Studies describing PBPK models for inorganic mercury salts. Toxicokinetic
differences among life stages (including gestation and postnatal development) will
be included where data are available.
Studies that meet the PECO criteria will be selected for further study quality evaluation and
the utility of these studies for dose-response as part of the evidence synthesis. In addition to the
PECO criteria, studies containing supplemental material that is also potentially relevant to the
specific aims will be tracked during the literature screening process. Table 6 presents major
categories of "potentially relevant supplemental material." This includes mechanistic information
from both mammalian and nonmammalian model systems, as well as ADME and toxicokinetic
information (including data informing bioavailability, such as solubility studies because solubility is
known to affect the absorption of inorganic mercury salts). These potentially relevant studies will
be "tagged" as such during screening to organize and prioritize evidence for consideration during
assessment development. Inclusion of these studies in the evidence synthesis will depend on their
likelihood to affect assessment conclusions for hazard identification or dose-response analysis and
will be based on their utility for addressing the identified key science issues (see Section 2.4) or
other important assessment uncertainties identified during review of the studies meeting the PECO
criteria.
This document is a draft for review purposes only and does not constitute Agency policy.
17 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Table 6. Major categories of "Potentially Relevant Supplemental Material"
Category
Evidence
Mechanistic
Studies reporting measurements related to a health outcome that inform the
biological or chemical events associated with phenotypic effects, in both
mammalian and nonmammalian model systems, including in vitro, in vivo,
ex vivo, and in silico studies.
ADME and
toxicokinetic
Studies designed to capture information regarding absorption, distribution,
metabolism, and excretion, including toxicokinetic studies. This category
includes studies of bioavailability and solubility because inorganic mercury salts
are soluble or insoluble in differing media. Such information may be helpful in
updating or revising the parameters used in existing PBPK models.
Exposure
characteristics
Exposure characteristic studies include data that are unrelated to toxicological
endpoints, but which provide information on exposure sources or measurement
properties of the environmental agent (e.g., demonstrate a biomarker of
exposure).
Mixture studies
Studies involving exposures to mixtures will be included if the exposure also
includes exposure to mercuric chloride, mercuric sulfide, or mercurous chloride.
Routes of exposure
not meeting PECO
criteria
Studies other than for oral and inhalation routes of exposure, (e.g., dermal
exposure).
Case reports or case
series
Descriptive studies of individual patients or small groups of individuals
presenting clinical symptoms or disease.
Reviews
Reviews and other summary documents (including other agency assessments).
This document is a draft for review purposes only and does not constitute Agency policy.
18 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
REFERENCES
Andres, P. (1984). IgA-IgG disease in the intestine of Brown-Norway rats ingesting
mercuric chloride. Clin Immunol 30: 488-494.
http://dx.doi.Org/https://doi.org/in.ini6/nn90-1229(84)90034-5.
ATSDR (Agency for Toxic Substances and Disease Registry). (1999). Toxicological profile
for mercury [ATSDR Tox Profile]. Atlanta, GA.
https://www.atsdr.cd c.gov/toxprofiles/tp.asp?id=115&.tid=24.
Barr. RD: Woodger. BA: Rees. PH. (1973). Levels of mercury in urine correlated with the
use of skin lightening creams. Am J Clin Pathol 59: 36-40.
http://dx.doi.org/10.1093/ajcp/59.1.36.
Bernaudin. JF: Druet. E: Druet. P: Masse. R. (1981). Inhalation or ingestion of organic or
inorganic mercurials produces auto-immune disease in rats. Clin Immunol 20: 129-
135. http://dx.dni.nrg/10.1016/0090-1 229(81 )901 70-7.
Bourgeois. M: Dooms-Goossens. A: Knockaert. D: Sprengers. D: Van Boven. M: Van
Tittelhoom, T. (1986). Mercury intoxication after topical application of a metallic
mercury ointment. Dermatology 172: 48-51.
http: / / dx.doi.org/10.1159/000249292.
Clarkson, TW. (1989). Mercury. Int J Toxicol 8: 1291-1295.
http: / / dx.doi.org/10.3109/10915818909009120.
Clarkson . TW: Friberg. L: Nordberg. GF: Sager. PR. (1988). Biological monitoring of toxic
metals. In TW Clarkson; L Friberg; GF Nordberg; PR Sager (Eds.), Biological
Monitoring of Toxic Metals. Boston, MA: Springer. http://dx.doi.org/10.10Q7/978-
1-4613-0961-1.
De Bont, B; T.auwerys, R; Govaerts, H; Moulin, D. (1986). Yellow mercuric oxide ointment
and mercury intoxication. Eur J Pediatr 145: 217-218.
h ttp: / / d x. d o i. o rg /1 0.1 007/BF00446069.
Druet, P; Druet, E; Potdevin, F; Sapin, C. (1978). Immune type glomerulonephritis induced
by HgC12 in the Brown Norway rat. Annales d'Immunologie 129C: 777-792.
Endo, T; Nakaya, S; Kimura, R. (1990). Mechanisms of absorption of inorganic mercury
from rat small intestine. III. Comparative absorption studies of inorganic mercuric
compounds in vitro. Pharmacol Toxicol 66: 347-353.
h ttp: / / d x. d o i. o rg /1 0.1111 /j.1 600-0773.1990.th00761 .x.
Friberg. E: Nordberg. F. (1973). Inorganic mercury a toxicological and epidemiological
appraisal. In Mercury, mercurials and mercaptans. Springfield, IL: Thomas, Charles
C. Publisher, Ltd.
Goyer. R. (1991). Toxic effects of metals. In Casarettand Doull's Toxicology. New York:
Pergamon Press.
This document is a draft for review purposes only and does not constitute Agency policy.
R-l DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
IARC (International Agency for Research on Cancer). (1993). Mercury and mercury
compounds. In IARC monographs on the evaluation of carcinogenic risk to humans
Beryllium, cadmium, mercury and exposures in the glass manufacturing industry
(pp. 311-325). https://monographs.iarc.fr/wp-content/uploads/2018/06/mono58-
8E.pdf.
Inouye, M; Kajiwara, Y. (1990). Placental transfer of methylmercury and mercuric mercury
in mice. Environmental Medicine 34: 168-172.
Kang-Yum. H: Oransky. SH. (1992). Chinese patent medicine as a potential source of
mercury poisoning. Vet Hum Toxicol 34: 235-238.
Kostial. K: Kello. D: Jugo. S: Rabar. I: Maljkovic. T. (1978). Influence of age on metal
metabolism and toxicity. Environ Health Perspect25: 81-86.
http://dx.doi.org/10.1289/ehp.782581.
Mckelvey. W: Jeffery. N: Clark. N: Kass. D: Parsons. PJ. (2011). Population-based inorganic
mercury biomonitoring and the identification of skin care products as a source of
exposure in New York City. Environ Health Perspect 119: 203-209.
http://dx.doi.org/10.1289/ehp.10Q2396.
Nielsen, JB; Andersen, 0. (1990). Disposition and retention of mercuric chloride in mice
after oral and parenteral administration. J Toxicol Environ Health 30: 167-180.
http://dx.doi.org/10.1080/15287399009531420.
NTP (National Toxicology Program). (1993). Toxicology and carcinogenesis studies of
mercuric chloride (CAS no 7487-94-7) in F344 rats and B6C3F1 mice (gavage
studies) (pp. 1-260). (NTP TR 408). Research Triangle Park, NC.
http://ntp.niehs.nih.gov/?ohjectid=070985B6-9C9D-8C67-4E459578E228B376.
Sin. YM: T,im. YF: Wong. MK. (1983). Uptake and distribution of mercury in mice from
ingesting soluble and insoluble mercury compounds. Bull Environ Contam Toxicol
31: 605-612. http://dx.doi.Org/https://doi.org/10.1007/hf01605483.
U.S. EPA (U.S. Environmental Protection Agency). (1987). Peer review workshop on
mercury issues [summary report] [EPA Report]. Cincinnati, OH.
U.S. EPA (U.S. Environmental Protection Agency). (1988). Drinking water criteria document
for inorganic mercury [EPA Report]. (ECAO-CIN-025).
U.S. EPA (U.S. Environmental Protection Agency). (1995). Integrated risk information
system (IRIS) chemical assessment summary for Mercuric chloride (HgC12).
Washington, DC.
https://cfpuh.epa.gov/ncea/iris/iris_documents/documents/suhst/0692_summary
.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2018). 2018 Edition of the drinking
water standards and health advisories tables. (EPA 822-F-18-001). Washington, DC:
Office of Water, U.S. Environmental Protection Agency.
https://www.epa.gov/sites/production/files/2018-
03/documents/dwtable2018.pdf.
IJSGS (U.S. Geological Survey). (1970). Mercury in the environment. (Professional Paper
713). http://dx.doi.org/10.3133/pp713.
WHO (World Health Organization). (2003). Elemental mercury and inorganic mercury
compounds. Human health aspects. In Concise International Chemical Assessment
Document, https://www.who.int/ipcs/puhlications/cicad/en/cicad50.pdf.
This document is a draft for review purposes only and does not constitute Agency policy.
R-2 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Yeoh. TS: T.ee. HS: T.ee. AS. (1989). Gastrointestinal absorption of mercury following oral
administration of cinnabar in a traditional Chinese medicine. Asia Pac J Pharmacol 4:
69-73.
This document is a draft for review purposes only and does not constitute Agency policy.
R-3 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
APPENDIX A. PHYSICAL AND CHEMICAL
PROPERTIES OF INORGANIC MERCURY SALTS
(COMPARISON OF MERCURIC CHLORIDE,
MERCUROUS CHLORIDE, AND MERCURIC SULFIDE)
Table A-l. Physical and chemical properties of inorganic mercury salts
(mercuric chloride, mercurous chloride, and mercuric sulfide)
Characteristics
Mercuric chloride
Mercurous chloride
(calomel)
Mercuric sulfide
(cinnabar)
CASRN
7487-94-7
10112-91-1
1344-48-5
Other names
HgCI2, mercury (II) chloride,
mercury perchloride
Hg2CI2, CI2Hg2, mercury (1)
chloride, dimercury
dichloride, mercury
subchloride, mercury
protochloride
HgS, mercury (II)
sulfide, vermilion
Molecular weight
271.492 g/mol
472.084 g/mol
232.652 g/mol
Physical
properties
Mercuric chloride is an odorless
white crystalline solid. Density
of 5.4 g/cm3 with a melting point
of 277°C. Slightly volatile at
ordinary temperatures. Can be
sublimed unchanged. Corrosive
to the mucous membranes.
Mercurous chloride is an
odorless white solid. Sinks
in water. Density is
7.15 g/cm3 with a melting
point of 525°C.
Mercuric sulfide is
an odorless red or
black solid.
Insoluble and sinks
in water. Density is
8.1 g/cm3 with a
melting point of
580°C.
Chemical
properties
Mercuric chloride volatizes
slightly at ordinary temperature
and appreciably at 100°C. It is
corrosive to mucous membranes
and used as a topical antiseptic
and disinfectant.
Mercurous chloride is an
irritant, cathartic, or
purgative. Seldom causes
systemic poisoning but
may be fatal if retained to
30-40 mg/kg. Contact
with eyes causes mild
irritation.
Mercuric sulfide
may cause allergic
skin reaction.
Oxidation state
+2
+1
+2
Solubility in water
69 g/L at 20°C
2.0 x 10"3 g/L at 25°C
1.0 x 10"3 g/L at
20°C
This document is a draft for review purposes only and does not constitute Agency policy.
A-l DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Table A-l. Physical and chemical properties of inorganic mercury salts
(mercuric chloride, mercurous chloride, and mercuric sulfide) (continued)
Characteristics
Mercuric chloride
Mercurous chloride
(calomel)
Mercuric sulfide
(cinnabar)
Absorption
Gl tract: 7-15%
Gl, <0.2%; oral
administration
Distribution
Kidney, liver, spleen. Does not
readily pass blood-brain barrier
or placenta because of its poor
lipid solubility.
Does not readily pass
blood-brain barrier or
placenta because of poor
lipid solubility.
Kidney, spleen, liver.
Does not readily
pass blood-brain
barrier or placenta.
Biotransformation
Hg2+ to Hg°
HgS to Hg2+ and
perhaps Hg2+ to Hg°
Excretion
Urine and feces
Urine and feces
References
https://pubchem.ncbi. nlm.nih.g
ov/compound/mercuric chlorid
https://pubchem.ncbi.nlm
.nih.gov/compounds/2495
https://pubchem.nc
bi.nlm.nih.gov/com
e#section=Top
6#section=Top
WHO (2003)
pound/62402#secti
on=Top
Gl = gastrointestinal.
1
This document is a draft for review purposes only and does not constitute Agency policy.
A-2 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
APPENDIX B. LITERATURE SEARCH STRATEGIES
Table B-l. Literature search strategies for inorganic mercury salts
Source
Search terms
Year
PubMed
Mercuric chloride: (((("Bichloride of mercurv" OR "Calochlor" OR "Corrosive
sublimate" OR "Dichloromercury" OR "HgCI2" OR "Mercuric chloride" OR
"Mercuric perchloride" OR "Mercury bichloride" OR "Mercury
chloromercurate (II)" OR "Mercury dichloride" OR "Mercury perchloride"
OR "Mercury (II) chloride"))) AND ("2018/01/01"[Date - Publication] :
"2019/02/15"[Date - Publication]))
1997-Feb 2019
Search results:
1,997
Mercuric sulfide: ((alpha-HgS OR Chinese red OR Cinnabar OR Ethiops
mineral OR Aethiops mineral OR HgS OR Mercuric sulfide OR Mercury (II)
sulfide OR Mercury (II) sulfide black OR Mercury (II) sulfide red OR Mercury
sulfide OR Mercury sulphide OR Vermilion)) AND
("2018/01/01"[Date - Publication] : "2019/02/15"[Date - Publication])
1997-Feb 2019
Search results:
1,200
Mercurous chloride: ((calogreen OR calomel OR chloromercuri OR CI2Hg2
OR mercury dichloride OR Hg2CI2 OR hydrochloric acid mercury salt OR
mercurous chloride OR mercury (1) chloride OR mercury chloride OR
mercury monochloride OR mercury protochloride OR mercury subchlorides
OR mild mercury chloride)) AND ("2018/01/01"[Date - Publication] :
"2019/02/15"[Date - Publication])
1997-Feb 2019
Search results:
2,612
WOS
Mercuric chloride: TS=("Bichloride of mercurv" OR "Calochlor" OR
"Corrosive sublimate" OR "Dichloromercury" OR "HgCI2" OR "Mercuric
chloride" OR "Mercuric perchloride" OR "Mercury bichloride" OR "Mercury
chloromercurate (II)" OR "Mercury dichloride" OR "Mercury perchloride"
OR "Mercury (II) chloride" OR "7487-94-7") AND PY=2018-2019
1997-Feb 2019
Search results:
3,888
Mercuric sulfide: TS=("alpha-HgS" OR "Chinese red" OR "Cinnabar" OR
"Ethiops mineral" OR "HgS" OR "Mercuric sulfide" OR "Mercury (II) sulfide"
OR "Mercury (II) sulfide black" OR "Mercury (II) sulfide red" OR "Mercury
sulfide" OR "Mercury sulphide" OR "Vermilion") AND PY=2018-2019
1997-Feb 2019
Search results:
3,862
Mercurous chloride: TS=("Calogreen" OR "Calomel" OR "Chloromercuri" OR
"CI2Hg2" OR "Dimercury dichloride" OR "Hg2CI2" OR "Hydrochloric acid
mercury salt OR Mercurous chloride" OR "Mercury (1) Chloride" OR
"Mercury chloride" OR "Mercury monochloride" OR "Mercury
protochloride" OR "Mercury subchloride" OR "Mild mercury chloride") AND
PY=2018-2019
1997-Feb 2019
Search results:
2,150
This document is a draft for review purposes only and does not constitute Agency policy.
B-l DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Table B-l. Literature search strategies for inorganic mercury salts
(continued)
Source
Search terms
Year
Toxline
Mercuric chloride:
@OR+("Bichloride+of+mercury"+Calochlor+"Corrosive+sublimate"+Dichlor
omercury+HgCI2+"Mercuric+chloride"+"Mercuric+perchloride"+"Mercury+
bichloride"+"Mercury+chloromercurate+(ll)"+"Mercury+dichloride"+"Merc
ury+perchloride"+"Mercury+(ll)+chloride"+@TERM+
@rn+7487-94-7)+@NOT+@org+pubmed+pubdart+@AND+@RANGE+yr+20
18+2019
1997-Feb 2019
Search results:
359
Mercuric sulfide:
@OR+("alpha-HgS"+"Chinese+red"+"Cinnabar"+"Ethiops+mineral"+"HgS"+"
Mercuric+sulfide"+"Mercury+(ll )+sulfide"+"Mercury+
(ll)+sulfide+black"+"Mercury+(ll)+sulfide+red"+"Mercury+
sulfide"+"Mercury+sulphide"+"Vermilion"+@TERM+@rn+1344-48- 5)+@N
OT+@org+pubmed+pubdart+@AND+@RANGE+yr+2018+2019
1997-Feb 2019
Search results:
72
Mercurous chloride:
(@OR+("Calogreen"+"Calomel"+"Chloromercuri"+"CI2Hg2"+"Dimercury+dic
hloride"+"Hg2CI2" +"Hydrochloric+acid+mercury+salt"+
"Mercurous+chloride"+"Mercury+(l)+Chloride"+"Mercury+chloride"+"Merc
ury+
monochloride"+"Mercury+protochloride"+"Mercury+subchloride"+"Mild+
mercury+chloride"
+@TERM+@rn+10112-91- l)+@AND+@RANGE+yr+1999+2018)+@NOT+@
org+pubmed+pubdart
1997-Feb 2019
Search results:
61
1
This document is a draft for review purposes only and does not constitute Agency policy.
B-2 DRAFT-DO NOT CITE OR QUOTE
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
//?/S Assessment Plan for Inorganic Mercury Salts
APPENDIX C. LITERATURE SEARCH METHODS
AND INITIAL RESULTS
The current assessment focuses on literature searches from 1997 (after publication of 1999
ATSDR toxicological profile but covering 2 previous years). This literature survey consisted of a
broad search from 1997 through February 2019 using chemical names (mercuric chloride,
mercurous chloride, and mercuric sulfide), Chemical Abstracts Service registry number (CASRN),
and synonyms. Three different databases including PubMed, Toxline, and Web of Science were
searched. The results of this literature search are documented and can be found on the Health and
Environmental Research Online (HERO) website on mercury salts project page
(https://heronet.epa.gov/lieronet/index.cfm/project/page/projectJd/2697).
Following the literature search from three different databases (PubMed, Toxline, and WOS),
preliminary screening was performed to remove the duplicates for each chemical. The studies
were then uploaded and sorted in SWIFT Review (Sciome Inc), a text-mining work bench for
systematic review, using a predetermined list of health outcomes and evidence streams. The
SWIFT Review filters that were applied focused on lines of evidence (human, animal, in vitro) and
health outcomes (cancer, cardiovascular, developmental, endocrine, gastrointestinal, hematological
and immune, hepatic, mortality, musculoskeletal, neurological, nutrition and metabolic, ocular and
sensoiy, renal, reproductive, respiratory, and skin and connective tissue). Following SWIFT review,
screening, studies were manually screened using Distiller (Distiller SR), another systematic review
tool. The studies were screened by title/abstract for relevance against the PECO criteria as
described in Section 3. Reviewed studies were placed into one of three categories: (1) PECO
relevant (oral and inhalation studies), (2) not PECO relevant, or (3) supplemental information
including various categories such as dermal and other routes of exposure, case-reports, mechanistic
studies, ADME/PBPK, mixture studies, reviews, bioavailability, nonmammalian, and other studies.
Mechanistic data can be informative to linking biomarkers to apical effects. The initial results of the
binning are shown in Figures in supplemental materials/Appendix (mercuric chloride, Figure D-l,
Figure D-4; mercuric sulfide, Figure D-2, Figure D-5; and mercurous chloride, Figure D-3, Figure
D-6), for oral and inhalation exposures, respectively. Many studies reported more than one health
effect/outcome category; therefore, there is not a one-to-one correspondence between the total
number of studies across the endpoints and the total number of studies identified in the screening
process. Following the title/abstract screening, PECO-relevant studies were tagged for full-text
screening. Remaining studies were either excluded as non-PECO-relevantor tagged as
supplemental. Once the studies were screened for full text, appropriate studies were categorized
for further evaluation to determine the dose-response relationships. Remaining studies were again
This document is a draft for review purposes only and does not constitute Agency policy.
C-l DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
tagged as non-PECO-relevant or supplemental. When necessaiy, the supplemental studies will be
evaluated further as supporting data for the assessment.
This document is a draft for review purposes only and does not constitute Agency policy.
C-2 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
APPENDIX D. INITIAL LITERATURE INVENTORY
SUMMARIES
Excluded by electronic screen
(n = 2370)
Additional Search Strategies (focus on
oral route of exposure)
Database Searches for Mercuric Chloride - oral (1997 to February 2019)
PubMed
(n = 1997)
WOS
(n = 3888)
ToxLine
(n = 359)
TITLE AND ABSTRACT
FULL TEXT
Full-Text Screening (Level2)
(n = 288)
Title & Abstract Screening (Levell)
(2649 records after duplicate removal)
not relevant to PECO (n = 59)
Excluded (n= 157)
not relevant to PECO (n = 1733)
Excluded (n = 2361)
Studies Considered Further (Level3)
(n = 131)
Human health effects studies (n = 2)
o Immunological (n = 2)
Animal health effect studies (n = 129)
o Cancer (n = 2), cardiovascular (n = 11), dermal (n= 1),
endocrine (n = 11), hematological (n = 23), hepatic (n =
43),immune (n = 16), lymphatic (n= 2), renal (n = 50),
gastrointestinal (n = 9), developmental (n = 4), neurological (n
= 29), musculoskeletal/ connective tissue (n = 2), reproductive
(n = 23), respiratory (n = 4), systemic/ whole body (n = 63),
urinary (n = 3), other (n = 42)
Tagged as supplemental
(n= 726)
• Mechanistic (n = 295)
• ADME/PBPK (n = 5)
• Non oral route of exposure
(n = 337)
• Human case reports and
case series (n = 11)
• Mixtures (n = 5)
• Reviews (n = 18)
• Non-mammalian (n = 65)
• Bioavailability (n = 50)
• Other (n = 25)
Figure D-l. Results of initial literature survey—database searches for
mercuric chloride for oral exposures.
This document is a draft for review purposes only and does not constitute Agency policy,
D-l DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Database Searches for Mercuric Sulfide - oral (1997 to February 2019)
f
PubMed
(n = 1200)
V.
y
wos
(n = 3862)
ToxLine
(n = 72)
Additional Search Strategies (focus on
oral route of exposure)
Excluded by electronic screen
(n = 2756)
TITLE AND ABSTRACT
Title & Abstract Screening (Levell)
(1956 records after duplicate removal)
Excluded (n = 1914)
not relevant to PECO (n = 1863)
FULL TEXT
Full-Text Screening (Level2)
(n = 42)
Excluded (n= 12)
• not relevant to PECO (n = 8)
Studies Considered Further (Level 3)
(n = 30)
Animal health effect studies (n = 30)
o hematological (n = 8), hepatic (n = 16), renal (n = 16),
gastrointestinal (n = 1), developmental (n = 1), immunological
(n = 1), neurological (n = 13), musculoskeletal/ connective
tissue (n = 1), reproductive (n = 1), sensory (n=l), Systemic/
whole body (n = 14), urinary (n=2), ADME/PBPK (n = 17),
cardiovascular (n = 1), other (n = 6)
Tagged as supplemental
(n= 55 )
• Mechanistic (n = 11)
• ADME/ PBPK(n= 19)
• Non oral route of exposure
(n = 7)
• Human case reports and
case series (n = 7)
• Mixtures (n = 4)
• Reviews (n = 23)
• Non-mammalian (n = 15)
• Bioavailability (n = 23)
• Other (n = 30)
Figure D-2. Results of initial literature survey—database searches for
mercuric sulfide for oral exposures.
This document is a draft for review purposes only and does not constitute Agency policy,
D-2 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Excluded by electronic screen
(n = 2453)
Additional Search Strategies (focus on
oral route of exposure)
Database Searches for Mercurous Chloride - oral (1997 to February 2019)
PubMed
(n = 2611)
WOS
(n = 2150)
ToxLine
(n = 61)
TITLE AND ABSTRACT
FULL TEXT
Full-Text Screening
(n = 1)
Title & Abstract Screening
(2172 records after duplicate removal)
Studies Considered Further
{n = 0)
not relevant to PECO (n = 0)
Excluded (n= 1)
not relevant to PECO (n = 2055)
Excluded (n = 2171)
Tagged as supplemental
(n= 117)
Mechanistic (n = 44)
ADME / PBPK (n = 3)
Non oral route of exposure (n = 25)
Human case reports and case series (n
= 7)
Mixtures (n = 2)
Reviews (n = 1)
Bioavailability (n = 1)
Other(n=68)
Figure D-3. Results of initial literature survey—database searches for
mercurous chloride for oral exposures.
This document is a draft for review purposes only and does not constitute Agency policy,
D-3 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Excluded by electronic screen
(n = 2370)
Additional Search Strategies (focus on
inhalation route of exposure)
Database Searches for Mercuric Chloride - inhalation (1997 to February 2019)
PubMed
{n = 1997)
WOS
{n = 3888)
ToxLine
{n = 359)
TITLE AND ABSTRACT
FULL TEXT
Full-Text Screening
(n = 61)
Title & Abstract Screening
(2649 records after duplicate removal)
not relevant to PECO (n = 1389)
Excluded (n = 2588)
not relevant to PECO (n = 46)
Excluded (n=60)
Studies Considered Further
(n = 1)
Human health effects studies
o Immunological (n = 1)
Tagged as supplemental
(n= 1227)
Mechanistic (n = 488)
ADME/PBPK (n = 20)
Non inhalation route of exposure (n =547)
Human case reports & case series (n = 17)
Mixtures (n = 2)
Reviews (n = 44)
Non-mammalian (n = 130)
Bioavailability (n = 23)
Other (n = 21)
Figure D-4. Results of initial literature survey—database searches for
mercuric chloride for inhalation exposures.
This document is a draft for review purposes only and does not constitute Agency policy,
D-4 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Excluded by electronic screen
(n = 2756)
Additional Search Strategies (focus on
oral route of exposure)
Database Searches for Mercuric Sulfide - inhalation (1997 to February 2019)
PubMed
(n = 1200)
WOS
(n = 3862)
ToxLine
(n = 72)
TITLE AND ABSTRACT
FULL TEXT
Full-Text Screening
(n = 7)
Title & Abstract Screening
(1956 records after duplicate removal)
not relevant to PECO (n = 1885)
Excluded (n = 1949)
not relevant to PECO (n = 1)
Excluded (n= 7)
Studies Considered
Further
(n = 0)
Tagged as supplemental
(n= 70)
Mechanistic (n = 14)
ADME / PBPK (n = 3)
Non oral route of exposure (n = 45)
Human case reports & case series (n = 8)
Mixtures (n = 2)
Reviews (n = 15)
Non-mammalian (n =2)
Bioavailability (n = 6)
Other(n = 0)
Figure D-5. Results of initial literature survey—database searches for
mercuric sulfide for inhalation exposures.
This document is a draft for review purposes only and does not constitute Agency policy,
D-5 DRAFT-DO NOT CITE OR QUOTE
-------
IRIS Assessment Plan for Inorganic Mercury Salts
Excluded by electronic screen
(n = 2453)
Additional Search Strategies {focus on
oral route of exposure)
Database Searches for Mercurous Chloride - inhalation (1997 to February 2019)
PubMed
(n = 2611)
WOS
(n = 2150)
ToxLine
(n = 61)
TITLE AND ABSTRACT
FULL TEXT
Full-Text Screening
(n = 3)
Title & Abstract Screening
{2171 records after duplicate removal)
not relevant to PECO (n = 2)
Excluded (n= 3)
not relevant to PECO (n = 1671)
Excluded {n = 2168)
Studies Considered
Further
(n = 0)
Tagged as supplemental
{n = 498)
Mechanistic (n =10)
ADME / PBPK (n = 1)
Non inhalation route of exposure (n = 22)
Human case reports and case series (n = 6
Mixtures (n = 1)
Reviews (n = 8)
Non-mammalian (n = 11)
Bioavailability (n = 0)
Other (n = 475)
Figure D-6. Results of initial literature survey—database searches for
mercurous chloride for inhalation exposures.
This document is a draft for review purposes only and does not constitute Agency policy,
D-6 DRAFT-DO NOT CITE OR QUOTE
------- |