*>EPA
United States
Environmental
Protection Agency
EPA/600/R-22/195F | July 2023 | www.epa.gov/risk
ORD Human Health Toxicity Value for
Lithium bis [(trifluoromethyl)sulfonyl]azanide (HQ-115)
(CASRN 90076-65-6 I DTXSID8044468)
Office of Research and Development
Center for Public Health and Environmental Assessment
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A United States
Environmental Protection
RhmiI Mm. Agency
EPA/600/R-22/195F
ORD Human Health Toxicity Value for
Lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
(CASRN 90076-65-6 | DTXSID8044468)
July 2023
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
DISCLAIMER
The human health assessment is intended to inform fit-for-purpose decision contexts
(e.g., site-specific screening, prioritization, and assessment) and was developed in response to a
request for site-specific technical support. The document provides hazard and dose-response
information about the adverse effect(s) of the chemical and derived toxicity value(s) based on the
available evidence, including the strengths and limitations of the available data. All users are
advised to review the information provided in this document to ensure that the value(s) used is
appropriate for the types of exposures and circumstances at the site in question and the risk
management decision(s) that would be supported by the assessment.
This human health assessment was developed by EPA's Office of Research and
Development (ORD) to respond to a request from the EPA Office of Enforcement and
Compliance Assurance (OECA), in support of site-specific decision-making under the purview
of the Safe Drinking Water Act. Other EPA programs or external parties who may choose to use
values derived in this fit-for-purpose assessment are advised that EPA/ORD resources will not
generally be used to respond to challenges, if any, pertaining to content/values used in a context
outside of the specific purpose or applicability domain for which it was derived.
This document has been reviewed in accordance with EPA policy and approved for
publication. The human health assessment has received internal peer review by two
EPA/ORD/CPHEA scientists and an independent external peer review by three scientific
experts outside of EPA. Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
AUTHORS, CONTRIBUTORS, AND REVIEWERS
Chemical Managers/ Authors
Elizabeth Oesterling Owens. PhD
Lucina Lizarraga. PhD
Jason C. Lambert, PhD, DABT
Contributors
Avanti Shirke, MPH
U.S. EPA, Center for Public Health and
Environmental Assessment
U.S. EPA, Center for Computational Toxicology
and Exposure
U.S. EPA, Center for Public Health and
Environmental Assessment
Production Support
Dahnish Shams
Jessica Soto-Hernandez
Ryan Jones
Samuel Thacker
Vicki Soto
Lauren Johnson
Primary Internal Reviewers
Kathleen Newhouse, PhD
J. Allen Davis, MSPH
Primary External Reviewers1
Gloria B. Post, PhD, DABT
Panagiotis G. Georgopoulos, PhD
Penelope A. Rice, PhD, DABT
Executive Direction
Wayne Cascio, MD
V. Kay Holt
Samantha Jones, PhD
Kristina Thayer, PhD
U.S. EPA, Center for Public Health and
Environmental Assessment
Student Services Contractor, Oak Ridge
Associated Universities (ORAU)
U.S. EPA, Center for Public Health and
Environmental Assessment
New Jersey Department of Environmental
Protection
Rutgers University
U.S. Food and Drug Administration
CPHEA Center Director
CPHEA Deputy Center Director
CPHEA Associate Director
CPHEA Chemical and Pollutant Assessment
Division Director
Questions regarding the content of this assessment should be directed to the EPA Office of Research
and Development (ORD) Center for Public Health and Environmental Assessment (CPHEA) website at
https://ecomments.epa.gov/.
1 Dr. Post and Dr. Rice conducted this review as independent consultants and not as a representative of the New
Jersey Department of Environmental Protection or the U.S. Food and Drug Administration, respectively.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
TABLE OF CONTENTS
BACKGROUND 1
HQ-115 QUALITY ASSURANCE 1
INTRODUCTION 3
METHODS 6
RESULTS 7
Literature Search and Screening Results 7
Human Studies 8
Animal Studies 9
Other Data 20
DERIVATION 01 REFERENCE VALUES 32
Derivation of Oral Reference Dose 32
Selection of the Chronic Reference Dose 38
CARCINOGENICITY ASSESSMENT 40
REFERENCES 41
APPENDIX A. ASYSTEMATIC LITERATURE SEARCH METHODS AND RESULTS 47
Methods 47
Populations, Exposures, Comparators, and Outcomes (PECO) Criteria and Supplemental
Material Tagging 47
Literature Search and Screening Strategies 47
Data Extraction of Study Methods and Findings 49
Study Evaluation 50
APPENDIX B. BENCHMARK DOSE MODELING RESULTS 55
MODELING PROCEDURE FOR CONTINUOUS NONCANCER DATA 55
Model Predictions for Increased Relative Liver Weight in Male Rats (Huntingdon Research
Center, 1993a) 56
Model Predictions for Increased Relative Liver Weight in Female Rats (Huntingdon
Research Center, 1993a) 58
Model Predictions for Increased Serum Alkaline Phosphatase (ALP) in Male Rats
(Huntingdon Research Center, 1993 a) 60
MODELING PROCEDURE FOR DICHOTOMOUS NONCANCER DATA 62
Model Predictions for Increased Hepatocyte Hypertrophy in Male Rats (ECHA, 2020r) 62
Model Predictions for Decreased Survival of Offspring at PND4 (ECHA, 2020h, y) 65
IV
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
TABLES
Table 1. Physical and Chemical Properties of HQ-115 and TFSI 4
Table 2. Summary of HQ-115 Genotoxicity Data 22
Table 3. Other Supporting Animal Toxicity Studies 28
Table 4. Data for Liver Effects in Adult Rats and Developmental Effect in Birthed Offspring from Rat
Toxicity Studies of HQ 115 Considered for BMDS Modeling 35
Table 5. Candidate PODs for Derivation of the Chronic RfD for HQ-115 36
Table 6. Candidate Chronic Reference Doses for HQ-115 38
Table 7. Uncertainty Factors for the Chronic RfD for HQ-115 (CASRN 90076-65-6) 39
Table 8. Confidence Descriptors for the Chronic RfD for HQ 115 (CASRN 90076-65-6) 39
Table 9. Summary of Noncancer Reference Values for HQ-115 (CASRN 90076-65-6) 40
Table A-l. PECO Criteria 52
Table A-2. Major categories of potentially relevant supplemental material 53
Table B-l. BMD Modeling Results for Increased Relative Liver Weight in Adult Male Sprague Dawley
Rats Exposed to HQ-115 for 28-days via Gavage 56
Table B-2. BMD Modeling Results for Increased Relative Liver Weight in Adult Female Sprague Dawley
Rats Exposed to HQ-115 for 28-days via Gavage 58
Table B-3. BMD Modeling Results for Increased Serum ALP in Adult Male Sprague Dawley Rats
Exposed to HQ-115 for 28-days via Gavage 60
Table B-4. BMD Modeling Results for Increased Hepatocyte Hypertrophy in Adult Male Sprague Dawley
Rats Exposed to HQ-115 for 29-days via Gavage 63
Table B-5. PND4 Offspring Survival Data Selected for Dose-Response Modeling for HQ-115 65
Table B-6. BMD Modeling Results for Decreased Survival of Offspring at PND4 Exposed to HQ-115 via
Gavage 67
FIGURES
Figure 1. Literature Search Flow Diagram for HQ-115 8
Figure 2. Study Evaluation for Animal Studies and All Health Outcomes 9
Figure 3. Liver Weights Following Oral Exposure to HQ-115 11
Figure 4. Liver Histopathology Following Oral Exposure to HQ-115 12
Figure 5. Select Blood Markers Related to Liver Function Following Oral Exposure to HQ 115 13
Figure 6. Liver Histopathology Following Oral Exposure to HQ-115 16
Figure 7. Pup Viability Index Following Oral Exposure to HQ-115 19
Figure B-l. Fit of Exponential 2 Model to Data for Increased Relative Liver Weight in Adult Male
Sprague Dawley Rats Exposed to HQ-115 for 28-days via Gavage (Huntingdon Research Center,
1993a) 57
Figure B-2. Fit of Exponential 2 Model to Data for Increased Relative Liver Weight in Adult Female
Sprague Dawley Rats Exposed to HQ-115 for 28-days via Gavage (Huntingdon Research Center,
1993a) 59
Figure B-3. Fit of Polynomial 3 Model to Data for Increased Serum ALP in Adult Female Sprague Dawley
Rats Exposed to HQ-115 for 28-days via Gavage (Huntingdon Research Center, 1993a) 61
Figure B-4. Fit of Multistage Degree 1 Model to Data for Increased Hepatocyte Hypertrophy in Adult
Male Sprague Dawley Rats Exposed to HQ-115 for 29-days via Gavage (ECHA, 2020r) 63
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Figure B-5. Fit of Probit Model to Data for Increased Hepatocyte Hypertrophy in Adult Male Sprague
Dawley Rats Exposed to HQ-115 for 29-days via Gavage 64
Figure B-6. Fit of Multistage Degree 1 Model to Data for Decreased Survival of Offspring at PND4s
Exposed to HQ-115 via Gavage (1(1 I A. 2020h), (IK II A. 202(h) 67
VI
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
COMMONLY USED ABBREVIATIONS AND ACRONYMS
AIC Akaike's information criterion
ALP alkaline phosphatase
ALT alanine aminotransferase
AST aspartate aminotransferase
BMCL benchmark concentration lower
confidence limit
BMD benchmark dose
BMDL benchmark dose lower confidence limit
BMDS Benchmark Dose Software
BMR benchmark response
BW body weight
CASRN Chemical Abstracts Service registry number
CBI nonconfidential business information
CERI Chemicals Evaluation and Research
Institute
CPHEA Center for Public Health and Environmental
Assessment
DTXSID DSSTox substance identifier
EPA Environmental Protection Agency
FT3 free triiodothyronine
FT4 free thyroxine
GGT y-glutamyl transferase
GLP Good Laboratory Practice
HbA 1 c form of hemoglobin linked to sugar
LIED human equivalent dose
HERO Health and Environmental Research
Online
IRIS Integrated Risk Information System
LOAEL lowest-observed-adverse-effect level
NLM National Library of Medicine
NOAEL no-observed-adverse-effect level
NTP National Toxicology Program
OECD Organization for Economic
Cooperation and Development
ORD Office of Research and Development
PBPK physiologically based
pharmacokinetic
PECO populations, exposures, comparators,
and outcomes
PFAS per- and polyfluoroalkyi substances
PFOA perfluorooctanoic acid
PFOS perfluorooctane sulfonic acid
PFPrA perfluoropropanoic acid
POD point of departure
PODhed human equivalent
QA quality assurance
RD relative deviation
RfC inhalation reference concentration
RfD oral reference dose
SD standard deviation
TGAb thyroglobulin antibody
TIAB title or abstract
TMAb thyroid microsomal antibody
TSH thyroid stimulating hormone
UF uncertainty factor
UFa interspecies uncertainty factor
UFc composite uncertainty factor
UFd
database uncertainty factor
UFh
intraspecies uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor UF s
subchronic-to-chronic uncertainty factor
U.S.
United States of America
WoS
Web of Science
Vll
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
BACKGROUND
The U.S. Environmental Protection Agency (EPA) Office of Research and Development
(ORD) under the Health and Environmental Risk Assessment (HERA) National Research
Program has developed a human health toxicity value for lithium bis[(trifluoromethyl)sulfonyl]
azanide (HQ-115); Chemical Abstract Services Registry Number (CASRN 90076-65-6). The
assessment was developed in response to a request for site-specific technical support and scoped
to help meet site-specific public health goals. The assessment provides qualitative and
quantitative toxicity information that can be used along with exposure information and other
important considerations, to assess potential health risks to determine if, and when, taking action
to address this chemical is appropriate.
The expressed purpose of this assessment is to provide support for risk-based decision-
making pertaining to chronic exposures to HQ-115 at sites or geographic locations or in specified
environmental media (e.g., water, soil, air). Several factors are considered during scoping and
problem formulation activities to ensure the assessment appropriately fits the intended purpose.
These factors include the anticipated end-user need, peer-review and public comment
requirements, and anticipated availability of hazard and dose-response evidence. Factors are
assessed and informed through direct conversations with the requesting office(s) (e.g.,
EPA/OECA).
Noncancer and cancer toxicity values are derived (when supported by data) after a
systematic review of the relevant scientific literature, an evaluation of available hazard and dose-
response information using established EPA guidelines on human health risk assessment, and
appropriate internal EPA and external independent peer reviews. To the extent possible based on
the currently available evidence, the objective of this assessment is to present the major
conclusions reached in the hazard identification and derivation of human health toxicity values
and to characterize the overall confidence in these conclusions and values. This assessment is not
intended to represent a comprehensive treatise on the chemical. For example, evidence pertaining
to occurrence, fate, transport, and potential ecotoxicity are not considered. Further, less emphasis
is placed on providing definitive judgments of the integrated weight of evidence.
HQ-115 QUALITY ASSURANCE
This work was conducted under the EPA Quality Program to ensure data are of known
and acceptable quality to support their intended use. Surveillance of the work by the assessment
managers and programmatic scientific leads ensured adherence to quality assurance (QA)
processes and criteria and to quick and effective resolution of any problems. The QA manager,
assessment managers, and programmatic scientific leads have determined this work meets all
EPA quality requirements. This human health assessment was written with guidance from the
Center for Public Health and Environmental Assessment (CPHEA) Program Quality Assurance
Project Plan (QAPP), the QAPP titled Umbrella Quality Assurance Project Plan for CPHEA Fit-
For-Purpose Toxicity Assessments (L-CPAD-0033369-QP-1-2), and the contractor-led QAPP,
titled Quality Assurance Project Plan-General Support of CPHEA Assessment Activities (L-
CPAD-0031961-QP-1-2). As part of the QA system, a quality product review is completed prior
to management clearance. During assessment development, a Technical Systems Audit was
performed on February 15, 2023, with no major findings.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
This assessment received internal peer review by two EPA/ORD/CPHEA scientists and
an independent external peer review by three scientific experts outside of EPA. External peer
review was managed by ERG (110 Hartwell Avenue Lexington, MA 02421) under contract EP-
C-17-017. The reviews focused on whether studies were correctly selected and interpreted and
adequately described for the purposes of this ORD assessment. The reviews also covered
quantitative and qualitative aspects of the toxicity value development and addressed whether
uncertainties associated with the assessment were adequately characterized.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
INTRODUCTION
Per- and polyfluoroalkyl substances (PFAS) are a large group of anthropogenic chemicals
that include the well-known C8 species, perfluorooctanoic acid (PFOA), perfluorooctane
sulfonic acid (PFOS), and thousands of other structurally diverse fluorinated species. The
universe of environmentally relevant PFAS, including parent chemicals, metabolites, and abiotic
degradants, is greater than 12,000 substances.2
PFAS have strong, stable carbon-fluorine (C-F) bonds, making them resistant to
hydrolysis, photolysis, microbial degradation, and metabolism (Ahrens. 2011; Buck et at.. 2011;
Beach et at.. 2006). The chemical structures of many PFAS make them repel water and oil,
remain chemically and thermally stable, and exhibit surfactant properties. These properties make
PFAS useful for commercial and industrial applications and purposes, but also make some PFAS
persistent in the human body and the environment (Calafat et at.. 2019; Calafat et at.. 2007). Due
to their widespread use, physicochemical properties, persistence, and bioaccumulation potential,
many PFAS occur in exposure media (e.g., air, water, sediment), and in tissues and blood of
aquatic and terrestrial organisms, and humans.
Humans are widely exposed to PFAS (Sunderland et at., 2019), and PFAS have been
shown to pose ecological and human health hazards (Fenton et at.. 2021); (DeWitt. 2015);
(Hekster et at.. 2003); (I. c. « i1 \ JO J l.\
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table 1. Physical and Chemical Properties of HQ-115 and TFSI
Properly or
Kndpoinl (unit)
IIQ-I15
11 SI
Reference
Structure
F
° F
0 \ II /
N— S (-—F
Li* 11 \
q r
p
"°fl '
0 \ 11/
nn— - —4—r
i, v
0 F
(US. EPA, 2023s)
CASRN
90076-65-6
82113-65-3
DTXSID
8044468
2045026
Synonyms
Lithium
bis[(trifluoromethyl)sulfonyl]azanide
Lithium
bis(trifluoromethanesulfonyl)azanide
Methane sulfonamide, 1,1,1 -trifluoro-N-
[(trifluoromethyl)sulfonyl]-, lithium salt
(1:1)
Methanesulfonamide, 1,1,1 -trifluoro-N-
[(trifluoromethyl)sulfonyl]-, lithium salt
Lithium Trifluoromethanesulfonimide
Fluorad Brand Lithium-
Trifluoromethanesulphonimide HQ-115
Fluorad HQ 115
FluorinertHQ 115
FluorinertHQ 115 J
1,1,1-Trifluoro-N-
(trifluoromethanesulfonyl)methanesulfonamide
1,1,1 -Trifluoro-N-
[(trifluoromethyl)sulfonyl]methanesulfonamide
Methanesulfonamide, 1,1,1 -trifluoro-N-
[(trifluoromethyl)sulfonyl] -
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Properly or
Knilpoinl (unit)
IIQ-115
11 SI
Reference
Molecular
formula
C2F6LiN04S2
C2HF6NO4S2
Molecular weight
(g/mol)
287.08
281.14
Physical
description
White powder
—
Huntingdon Research
CenteLi!993d)
Odor
NA
NA
Melting point (°C)
232.0 - 233.0 (experimental)
51.5 (experimental)
HO-115: Hiinti ngdo n
Research Center
(1993d): TFSI: U.S.
f2023)
Boiling point (°C)
308 (predicted average)
90.5 (experimental)
(U.S. EPA. 2023)
Density (g/cm3)
2.1984 (experimental)
1.94 (predicted average)
HO-115: Hiinti ngdo n
Research Center
(1993d): TFSI: (U.S.
2023)
Vapor pressure
(Pa at 25°C)
4 x 10"6
0.270 (mmHg) (predicted average)
HO-115: Hiinti ngdo n
Research Center
(1993d): TFSI: U.S.
f2023)
Henry's law
constant
3.13 x lo 5 (predicted average)
3.13 x 10~5 (predicted average)
(U.S. EPA. 2023)
Water solubility
(g/L at 20°C)
1.73 x 103
0.931 (mol/L) (predicted average)
HO-115: Hiinti ngdo n
Research Center
(1993d): TFSI: U.S.
f2023)
Log Kow (at 19°C)
-1.46
1.96 (predicted average)
Bioconcentration
factor
9.23 (predicted average)
9.23 (predicted average)
(U.S. EPA. 2023)
NA - Not available
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
METHODS
For this assessment, the general systematic review steps common to other assessments
(e.g., in Integrated Risk Information System [IRIS]) were applied, including the development of
populations, exposures, comparators, and outcomes (PECO) criteria for inclusion and literature
search and screening of multiple databases for relevant articles.
Briefly, methods used here are consistent with the ORD Staff Handbook for Developing
IRIS Assessments (Version 2.0, referred to as the "IRIS Handbook") ( 2022). These
methods were reviewed by the National Academy of Sciences (NASEM. 2021. 2018) and used
in other peer-reviewed systematic reviews (Yost et at.. 2019; Radke et at.. 2018). The purpose of
this human health assessment is to develop scientifically supported chronic toxicity values,
where data are available. Less emphasis is placed on providing definitive judgments of the
integrated weight of evidence.
The systematic review methods used to collect epidemiologic and toxicological evidence
for HQ115 (and TFSI) are described in detail in Appendix A. In addition to database searches,
nonconfidential business information (non-CBI) industry studies were identified that included
toxicological evidence for HQ-115. Since February 2020, EPA has requested, pursuant to section
308 of the Clean Water Act, 33 U.S.C. § 1318, that 3M provide information on its use and
possible release of certain PFAS, such as HQ-115. Under that agreement, 3M shared internal
files of memos, reports, interim or final data summaries or studies, correspondence, etc. that
included non-CBI content for HQ-115. The available information for HQ-115 received from 3M
was screened for relevance to the PECO criteria (see Figure 1). Literature identified as relevant
from the database searches or non-CBI data repositories underwent data extraction and study
evaluation (see documentation in HAWC: https://hawcprd.epa.eov/assessment/100500265/
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
RESULTS
Literature Search and Screening Results
The literature searches yielded 3,089 unique references for HQ-115 and TFSI. As shown
in the literature search diagram below (see Figure 1), seven animal studies meeting the PECO
criteria and thirty supplemental studies were identified. No human studies were identified. All
studies meeting PECO criteria evaluated HQ-115 exposure and not TFSI. The database of animal
toxicity studies consists of seven oral exposure studies in rats: one 7-day range finding study
(Huntingdon Research Center. 1992b). two 28/29-day studies (ECHA. 2Q20r; Huntingdon
Research Center. 1993a), a one-generation reproductive/developmental study (summarized in
two reports) (ECHA, 2020h, y), and three acute studies (EC 320e, f, g; 3M. 1988). The 7-
day range finding study and acute studies provide limited information for the evaluation of
potential health effects after repeat-dose toxicity and the derivation of a chronic oral reference
dose (RfD). Therefore, these studies were considered supplemental information and summarized
under "Other Data." Of the studies tagged as supplemental in Figure 1, eight were genotoxicity
studies (see Table 2 for more details) and thirteen were non-oral/inhalation studies (i.e., three
evaluated toxicities of HQ-115 after a single dermal dose, three evaluated skin
irritation/corrosion, three evaluated skin sensitization, and four evaluated ocular irritation; see
Table 3 for more details). These studies were also summarized under "Other Data." The
remaining supplemental studies in Figure 1 included two duplicate reports of PECO-relevant
studies and seven abstracts with relevant supplemental information (e.g., genotoxicity, ADME
and non-oral/inhalation route) but no underlying data; the latter were not advanced for evidence
synthesis.
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Human Health Toxicity Values for lithium bis[(trifhioromethyl)sulfonyl]azanide (HQ-1J5)
Lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)*
(CASRN 90076-65-6)
Peer and Gray Literature Search
(November 2022)
PubMed
(n = 1,423)
TEDX
(n = 0)
WoS
(n = 6,487)
ECHA
(n = 44)
CEBS
(n = 0)
ToxVal
(n = 19)
After deduplication n = 3,089
T
Other
Selected non-CBI
3M Studies
Submitted to EPA )
(n = 6)
REVIEWED FOR PECO
Figure 1. Literature Search Flow Diagram for IIQ-115
*The systematic literature search and review included the desalted amide of HQ-115, 1J J-Trifluoro-N-
Ktrifluorometln l)sulfoiiyl|niclhancsulfonamide (TFSI; CASRN 82113-65-3)
Human Studies
No human studies were identified that examine health effects of HQ-115.
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HO-115)
Animal Studies
The database of animal toxicity studies informing potential health effects associated with
repeat-dose exposure to HQ-115 includes three gavage studies in rats: two 28/29 day studies
(Huntingdon Research Center. 1993a); (ECHA. 2020r) and a one-generation
reproductive/developmental study (summarized in two reports) (ECHA, 2020h, y). The 28-day
study by Huntingdon Research Center (1993a) was rated as high confidence for all endpoints,
while the 29-day study and one-generation reproductive/developmental study were rated as low
confidence (ECHA 2020h. y); (ECHA 2020r) (see Figure 2). Concerns contributing to the low
confidence rating for the ECHA (2020h. 2020y) studies included issues regarding observational
bias for some endpoints (i.e., clinical signs, fetal malformations, neurobehavior), selective
reporting, chemical administration, and exposure characterization (limited information on source
and purity of test material), outcome assessment, and results presentation. Details on methods of
endpoint assessment and results were limited. Additionally, most data were provided
qualitatively, and the data that were provided quantitatively were incomplete (i.e., lack of
information on variances, sample sizes and/or statistical analyses).
5
Legend
| Good (metric) or High confidence (overall)
Adequate (metric) or Medium confidence (overall)
Deficient (metric) or Low confidence (overall)
Critically deficient (metric) or Uninformative (overall;
Not reported
Multiple judgments exist
ECHA, 2020r -
ECHA, 2020h, y -
Huntingdon Research Center, 1993 -
+*
-
-
+*
-
Figure 2. Study Evaluation for Animal Studies and All Health Outcomes.
Interactive figure and additional study details available on HAWC.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Huntingdon Research Center (1993a)
Male and female 5-week-old Crl: CD (Sprague-Dawley) BR VAF Plus rats (5/group)
were administered 0, 1.67, 10, or 60 mg/kg-day HQ-115 via gavage for 28 consecutive days
(Huntingdon Research Center. 1993a). Five additional control and high-dose male and female
rats were maintained for a 14-day recovery period. The study was conducted according to OECD
and GLP guidelines and evaluated clinical signs, body weights, food intake, hematology, blood
chemistry, urinalysis, organ weights (adrenals, brain, liver, kidneys, spleen, testes with
epididymides, and ovaries) and histopathology (adrenals, liver, heart, kidneys, spleen, and any
other abnormal tissue). As noted previously, there is high confidence in the study with no
significant concerns or deficiencies in any of the study quality domains evaluated (see Figure 2).
During the exposure period, no statistically significant effects on body weight or food
intake were reported in rats up to 60 mg/kg-day, except for a 5% increase in cumulative food
intake in females exposed to 60 mg/kg-day. During the recovery period, body weight gain was
significantly lower (32%, p < 0.05) in females treated with 60 mg/kg-day compared to controls.
No mortalities occurred in any group, and no clinical signs of toxicity were observed in the 1.67
mg/kg-day group. Clinical signs of toxicity occurred in both males and females at 10 mg/kg-day,
including piloerection (i.e., bristling of fur; 1/5 males and 1/5 females), which was accompanied
by hypersensitivity (not further specified) and abnormal gait only for the affected female. In the
60 mg/kg-day group, clinical signs of toxicity included piloerection (10/10 males and 10/10
females), hypersensitivity (10/10 males and 10/10 females), abnormal gait (9/10 males and 10/10
females), body tremors (4/10 males), lethargy (4/10 males), and fur loss (3/10 males). No clinical
signs were observed in the controls and in animals exposed to 60 mg/kg-day during the recovery
period.
Increases in liver weights (absolute and relative to body weight) were observed in males
and females (see Figure 3) at the highest dose (60 mg/kg-day). Relative liver weight3 increased
significantly by 46% in males and 49% in females (p < 0.001); similar changes in absolute liver
weight were observed. Relative, versus absolute, liver weight is generally the preferred metric in
the presence of body weight differences among groups, based on its proportional relationship to
body weight (Bailey et at.. 2004). Changes in liver weights resolved after the recovery period.
3 Study authors reported group mean values for "adjusted" (i.e., relative) liver weights but did not provide a measure
of variance. Relative liver weights (g/lOOg) were calculated for the purposes of this assessment using individual
animal body weight and absolute liver weight data. One-way ANOVA was used to evaluate differences in mean
vales among treatment groups, followed by Holm-Sidak t-tests for pairwise comparisons (control vs treatment
groups). Refer to HAWC Huntingdon Research Center (1993a) for additional details.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Study Name
Huntingdon Refw.iich Cenifif, 1993, 7376324 Oral Lw Weight, Rrtisiw Rat, Crl CdiSiiiBr Vat/Plus j - s g/100g
Study Design Endpoint Name AnimaS Description Response Units Dose
(mg^kg-day)
HQ-115 Liver Weights
Rat, Crl CdtSd) Br VafPlust ! fj'IGOp
, 0 Percent tontrc» t<
| 0 Statistically sigiiti'
I: 95"- Ci
10 20 30 40 50 60 70
Percent Control Response
Figure 3. Liver Weights Following Oral Exposure to HQ-115.
Interactive figure available on HAW €
The liver weight increases were accompanied by noticeable enlargement of the liver at
necropsy in the 60 mg/kg-day groups (5/5 males and 3/5 females). Microscopic examination of
the liver revealed minimal to moderate generalized hepatocyte hypertrophy (5/5 males and 4/5
females) and centrilobular hepatocyte hypertrophy (1/5 females). Centrilobular hepatocyte
vacuolation was observed in 1/5 males at 60 mg/kg-day and extramedullar hematopoiesis was
observed in the liver of males (2/5) at 1.67 mg/kg-day and females (1/5) at 10 mg/kg-day, both
lesions graded as minimal. These liver lesions were not observed in the controls or any other
dose groups (see Figure 4). Extramedullar hematopoiesis is uncommon in adult rats and may be
indicative of potential hepatocyte degeneration, pigment deposition, and/or fatty changes
(Marompot. 2014). Following the recovery period, an enlarged liver was observed in one out of
five males in the 60 mg/kg-day group; however, livers were no longer visibly enlarged in
females, and there was no evidence of hepatocyte hypertrophy. After recovery, incidence of
extramedullar hematopoiesis (graded as minimal) was similar in the controls and in males
exposed to 60 mg/kg-day (1/5). In females, minimal extramedullar hematopoiesis was notably
higher in the 60 mg/kg-day group compared to the control group (1/5 at 0 mg/kg-day versus 4/5
at 60 mg/kg-day). Capsular inflammator cells (graded as minimal) were reported in 1/5 males
exposed at 60 mg/kg-day. Data for the recover period is not shown in Figure 4. Overall, the
results suggest a coherent pattern of liver injur with some evidence of hepatocyte degeneration
(i.e., extramedullar hematopoiesis) after short-term HQ-115 exposure.
11
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HQ-115)
Study Name Study Design
Endpoint Name
Animal Description
Dose
(mg/kg-day)
Incidence
HQ-115 Liver Histopathology
Huntingdon Research Center, 1993, 7376324 28-Day Oral
Centrilobular Hepalocyte Hypertrophy
Rat, Crt:Cd(Sd) Br Vaf/Plus (• )
0
0/5 (0.0%)
ll I Response
1.67
0/5 (0.0%)
I I
10
0/5 (0.0%)
60
1/5 (20.0%)
I
Generalized Hepatocyte Hypertrophy
Rat, CrlCd(Sd) Br Vaf/Plus (cJ>
0
0/5 (0.0%)
1.67
0/5 (0.0%)
10
0/5 (0.0%)
60
5/5 (100.0%)
I
Rat, Crl:Cd(Sd) Br Vaf/Plus (-)
0
0/5 (0.0%)
1.67
0/5 (0.0%)
10
0/5 (0.0%)
60
4/5 (80.0%)
I
Centrilobular Hepatocyte Vacuolation
Rat, Cri:Cd(Sd) Br Vaf/Plus (o)
0
0/5 (0.0%)
1.67
0/5 (0.0%)
10
0/5 (0.0%)
60 1/5 (20.0%)
I
Extramedullary Hematopoiesis
Rat. Cr1:Cd(Sd) Br Vaf/Plus (#)
0
0/5 (0,0%)
1.67
2/5 (40.0%)
~l
10
0/5 (0.0%)
60 0/5 (0.0%)
Rat, Crl:Cd(Sd) Br Vaf/Plus (••)
0
0/5 (0.0%)
1.67
0/5 (0.0%)
10
1/5 (20.0%)
I
60
0/5 (0.0%)
i
1
2 3 4 5 6 7
Incidence
Figure 4. Liver Histopathology Following Oral Exposure to HQ-115.
Interactive figure available on HAWC
Serum enzyme and protein levels were also examined in the 28-day rat study. Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) (i.e., glutamic pyruvic
transaminase (GPT) and glutamic oxaloacetic transaminase (GOT)) are serum biomarkers of
hepatocellular damage, while alkaline phosphatase (ALP) and gamma-glutamyl transferase
(GGT) are markers of hepatobiliary damage. In males, ALP was increased significantly at the
highest dose (32% at 60 mg/kg-day, p < 0.01) (see Figure 5). No dose-related or statistically
significant changes in the levels of ALT, AST, and GGT were found in either males or females.
Serum albumin levels were significantly increased in the high-dose male and female groups (14-
15%, p < 0.01), and serum globulin was significantly decreased in the high-dose male group
(15%, p <0.01) and in all female groups (6- 11%, p < 0 .05) but total serum protein levels were
unaffected by exposure (Figure 5). Changes in blood proteins such as serum albumin/globulin
(A/G) ratio, which can reflect issues with the liver, kidneys, or other organs (Whalan. 2015). was
significantly increased in a dose-dependent manner in all dose groups in males and in females
(10-35%, p < 0.05). Although results were not always coherent across endpoints, changes in
some serum biomarkers provide support for potential liver damage in HQ-115-exposed animals
(i.e., increased ALP and A/G ratio).
12
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HQ-115)
Study Name Study Design Endpoint Name Animal Description Response Units Dose HQ-115 Select Clinical Chemi
(mg/kg-day)
stry
Huntingdon Research Center, 1993, 7376324 28-Day Oral Alkaline Phosphatase (ALP) Rat. Crt:Cd(Sd) BrVaf/Plus ( I) mil/ml 0
% Percent control response
O Statistically significant
H 95% CI
1.67
1 1
10
60
Rat, Cr1:Cd(Sd) Br Vaf/Plus (V) mil/ml 0
1 • 1
1.67
• 1
10
1 • 1
60
• 1
Albumin (A) Rat. Cr1:Cd(Sd) Br Vaf/Plus (. y) g/dL 0
1.67
H
~H
10
60
Rat, Cr1:Cd(Sd) Br Vaf/Plus (?) g/dl 0
1—#H
1.67
10
60
> • 1
Globulin (G) Rat, Crl:Cd(Sd) Br Vaf/Plus ( 5) g/dL 0
M
M
1.67
10
!-•-
60
Rat. Cr1:Cd(Sd) Br Vaf/Plus (?) g/dl 0
H
H
1.67
1 • 1
10
I--#-
60
Albumin/Globulin (A/G) Ratio Rat, Cr1:Cd(Sd) Br Vaf/Plus ( -!) Unitless 0
1.67
10
t • 1
60
1 • 1
Rat. Cri:Cd(Sd) Br Vaf/Plus (V) Unitless 0
1.67
,
10
¦ • i
60
¦»i
0
0 -20 -10 0 10 20 30 40 50 60 70
Percent Control Response
Figure 5. Select Blood Markers Related to Liver Function Following Oral Exposure
to HQ 115.
Interactive figure available on HAWC
There were other statistically significant effects observed in the blood of HQ-115
exposed male and female rats. Cholesterol and triglyceride levels were significantly decreased in
high-dose males (60% and 42%, respectively; p < 0.01), and cholesterol levels were decreased in
all female dose groups in a dose-dependent manner (16-19%, p < 0.05). Decreases in serum
lipids (i.e., triglycerides and cholesterol) have been observed in animals with exposure to other
PFAS (ATSDR. 2021). although the specific biological significance of these changes is unclear.
In addition, thrombotest time (which measures prothrombin time [PT]) was significantly
increased in males exposed to >10 mg/kg-day (14-23%) in a dose-related manner, although it
was not accompanied by changes in platelets. It is noted that the liver is responsible for the
synthesis of most clotting factors.
Kidney-related effects were also reported in rats after HQ-115 exposure (HAWC link).
Statistically significant increases (11%) in relative kidney weights were reported in males at the
highest dose. Similarly, absolute kidney weights in males and females exposed to 60 mg/kg-day
were increased by 11% and 9%, respectively; these changes were not statistically significant but
were considered biologically significant (i.e., a >10% increase in absolute and relative liver and
kidney weight is considered biologically significant by the EPA for the purposes of this
assessment). In general, the kidney weight changes did not show a dose-response gradient and
were not accompanied by any histological lesions. Effects in clinical biomarkers relevant to
13
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
kidney function were also reported. In the 60 mg/kg-day groups, significantly increased blood
urea nitrogen (BUN) was observed in males and females (33% and 27%, respectively; p < 0.01).
Urinary pH was statistically significantly decreased (6—9%, p < 0.05) in both sexes exposed to
>10 mg/kg-day, and urine volume increased by 38% in males exposed to 60 mg/kg-day (p <
0.05). Following the 14-day recovery period, urine pH remained statistically significantly
decreased in rats previously exposed to 60 mg/kg-day; however, no changes in kidney weight or
other biochemical indicators of kidney toxicity (i.e., BUN and urine volume) in either the blood
or urine were observed. Although results were not coherent across all endpoints, increased
kidney weight and altered kidney-related clinical biomarkers (i.e., increased BUN and decreased
urinary pH in males and females and increased urine volume in males) at the high dose suggest
potential kidney toxicity following HQ-115 exposure.
There were other health effects observed in rats after 28-day exposure, but they generally
occurred at the highest dose only, were sporadic, or were not supported by corroborative
evidence of toxicity. For example, in the 60 mg/kg-day males, absolute spleen weights were
significantly increased by 21% (p < 0.05) and relative spleen weights were similarly increased
(20%>), although the changes were not statistically significant. The increases in spleen weights
did not show a dose-response gradient and histological findings in the spleen were restricted to
minimal extramedullary hematopoiesis observed in one high-dose male. Blood glucose
concentration was significantly increased (12%, p < 0.05) in high-dose males only. Blood
chloride concentrations were significantly decreased in males in the two highest dose groups, but
only by 2% and 1%, respectively (p < 0.05). In the 60 mg/kg-day females, potassium
concentration was 16% decreased (p < 0.01). None of these hematological changes persisted into
the recovery period.
Additional changes that were not observed in animals evaluated immediately after
exposure ended were seen in the recovery groups. Absolute brain weight was increased 7% in
recovery males previously dosed with 60 mg/kg-day. In addition, enlarged lymph nodes were
observed in 4/5 recovery male rats dosed with 60 mg/kg-day and in 1/5 recovery control males.
Increased globulin and total protein levels and decreased absolute spleen weight (17%) were
observed in recovery female rats dosed with 60 mg/kg-day. The biological significance of these
effects is unclear in the absence of corroborative findings, including from histopathological
evaluations of the brain, lymph nodes and spleen.
Overall, the findings in the high confidence study by Huntingdon Research Center
3 a) showed coherent evidence of liver effects in male and female rats following 28-days of
exposure to HQ-115 mostly at the highest dose (60 mg/kg-day), including increased relative liver
weights, hepatocyte lesions (mainly increased hepatocyte hypertrophy and possible degenerative
changes [extramedullary hematopoiesis]), and some changes in serum biomarkers related to liver
damage (primarily increased ALP in males). Clinical signs of toxicity (piloerection,
hypersensitivity, abnormal gait, body tremors, lethargy, and fur loss) and indications of kidney
toxicity (e.g., increased organ weight; increased BUN) were also reported in males and females
at the highest dose (60 mg/kg-day).
ECHA (202Or)
A chemical registrant 29-day study is summarized on the European Chemical Agency
(ECHA) website in which the toxicity of HQ-115 after oral exposure in rats was evaluated
14
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
(ECUA, 2020r). Male and female 6-week-old Sprague-Dawley rats (5/group) were administered
0, 15, 45, or 90 mg/kg-day HQ-1 15 via gavage for 29 consecutive days (ECUA. 2020f). Five
additional control and high-dose male and female rats were maintained for a 14-day recovery
period. The study was conducted according to OECD and GLP guidelines and evaluated clinical
signs, functional observational battery, body weights, food intake, hematology, blood chemistry,
urinalysis, organ weights, and histopathology. The original source studies were not available,
resulting in a low confidence rating based on deficiencies in several study evaluation domains
(see Figure 2), including the lack of details on methods of endpoint assessment and presentation
of results in the available ECHA study summaries. In particular, details pertaining to organs
weighed, tissues examined for histopathology, and blood chemistry and urinalysis were not
reported, nor were the specific methods used for in-life or toxicological assessment reported;
most data were reported qualitatively. Group means were provided for body weights, food intake
and hematology but no information on variances or sample sizes was included.
Two mortalities in females in the high dose group occurred immediately after anesthesia
for blood collection and were considered to be accidental.
During the exposure period, slightly reduced body weight gains were reported in males
and females in the 45 mg/kg-day groups (8% males and 12% females) and in males in the 90
mg/kg-day group (10%); however, an increase in body weight gain was reported for females in
the 90 mg/kg-day group (62%). The increase in body weight gain in females in the 90 mg/kg-day
group was accompanied by significantly increased food consumption (39%, p < 0.01) during the
treatment period. During the recovery period, no significant effects on body weight gain were
reported, but a slightly higher food consumption was reported for both males and females.
There were no clinical signs of toxicity reported for the 15 mg/kg-day group. Clinical
signs of toxicity occurred in both males and females at 45 mg/kg-day, including aggressive
behavior (1/5 females) and hunched posture (1/5 males). At 90 mg/kg-day, clinical signs of
toxicity included piloerection (3/5 males), ptyalism (i.e., overproduction of saliva) (1/5 males
and 1/5 females), hunched posture (1/5 males), and aggressive behavior often associated with
hypersensitivity to touch (3/10 males and 2/10 females). From the functional observation battery,
a slight increase in motor activity in males and females, withdrawal following touch escape in
males, and absence of auditory startle reflex in males were also observed in the animals exposed
to 90 mg/kg-day (data not reported).
Increases in liver weights (absolute and relative) were reported in males in the two
highest dose groups and in females in the highest dose group (data not reported). Changes in
liver weights resolved after the recovery period. The liver weight increases were accompanied by
noticeable enlargement of the liver at necropsy in males in the 45 mg/kg-day group (3/5) and in
the 90 mg/kg-day groups (4/5 males and 4/7 females) along with several grey or white areas on
the liver. These changes were no longer present after the recovery period. Microscopic
examination of the liver revealed hepatocellular hypertrophy in males in the 45 mg/kg-day group
(4/5) and in the 90 mg/kg-day groups (5/5 males and 4/7 females). This liver lesion was not
observed in the controls or in any animal of the 15 mg/kg-day groups (Figure 6). It was not
reported whether these microscopic changes were resolved following the recovery period.
15
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HQ-115)
Study Name Study Design Endpoint Name Animal Description Dose Incidence
(mg/kg-day)
HQ-115 Liver Histopathology
ECHA 2020, 8803688 29-Day Oral Hepatocellular Hypertrophy Rat, Sprague-Dawley (c5) 0 0/5 (0.0%)
| |Response
15 0/5(0.0%)
45 4/5 (80.0%)
i
90 5/5(100.0%)
Rat, Sprague-Dawley (J) 0 0/5(0.0%)
15 0/5(0.0%)
45 0/5 (0.0%)
90 4/7(57.1%)
i
I I I I i I [ i I
0.5 1 1.5 2 2.5 3 3.5 4 4.5
Incidence
Figure 6. Liver Histopathology Following Oral Exposure to HQ-115.
Interactive figure available on HAWC
Serum enzyme levels were examined in the 29-day rat study, but results were only
reported qualitatively. At 90 mg/kg-day, ALT (i.e., GPT) was significantly increased in males
and females, and ALP was significantly increased in males (p < 0.01). It is unclear whether AST
(i.e., GOT) levels were measured in the study. Effects on other clinical biomarkers relevant to
liver function were also reported. The A/G ratio and albumin levels were increased in males and
females in the high-dose groups. In addition, cholesterol and triglyceride levels were "slightly to
moderately" decreased (p < 0.01%) in males and females of all dose groups in a dose-dependent
manner.
Some variations were observed in the hematological parameters of exposed animals, but
many of the changes were either slight or lacking a clear dose-response relationship (HAWC
link); therefore, the biological significance of these effects is unclear. In the 45 and 90 mg/kg-
day dose groups, white blood cell (WBC) counts were increased (24-39% males and 16-37%
females), driven by increased neutrophils (25-51% males and 38-59% females) and lymphocytes
(19-43% males and 12-34% females). Red blood cell (RBC) counts were slightly decreased in
all dose groups (6-8% males and 5-9% females), and at 45 and 90 mg/kg-day, decreased
hemoglobin (4% males and 5-6% females) and decreased packed cell volume (5% males and 5-
7% females) were also observed.
Additional health effects observed in rats following the 29-day exposure generally
occurred at the highest dose only. Blood creatinine levels were slightly decreased in males and
females exposed to 90 mg/kg-day, but no treatment-related effects were reported in urinalysis
parameters (data not reported). Blood urea levels were slightly increased in males and slightly
decreased in females of all dose groups (data not reported). It is unclear if the kidneys were
weighed or examined for histopathology. In females, an increased incidence of thyroid follicular
cell hypertrophy (3/7) and decreased diameter of the follicular lumen (3/7) were observed at 90
mg/kg-day. These microscopic findings were also observed in males at the highest dose, but the
incidence was equivalent to that of the controls (2/5). An increased incidence of dilated lumen in
the uterus (4/7) was observed in females of the 90 mg/kg-day group and in 1/5 females in the 45
mg/kg-day; this was not observed in the control or low dose group. This effect was attributed by
study authors to variations in the estrous cycle, but no other details were provided. In addition,
minimal foamy alveolar macrophages were observed in the lungs of all males and two females in
the 90 mg/kg-day group, compared to only one male and one female in the control group.
16
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Despite deficiencies in several study evaluation domains (including lack of details on
methods of endpoint assessment and presentation of results; Figure 2) that to some extent limit
interpretation of results, the low confidence ECU A. (2Q20r) study provided sufficient information
to identify potential health effects associated with short-term duration oral exposure to HQ-115.
The study reported coherent liver effects in male and female rats at > 45 mg/kg-day across organ
weights (increased absolute and relative liver weights), histopathology (hepatocyte hypertrophy)
and serum biomarkers of liver damage (primarily increased ALT and ALP). It should also be
noted that the liver effects are consistent with the findings from the high confidence study by
Huntingdon Research t ^itpt > I^Oa). Other possible exposure-related effects were observed in
rats mostly at the highest dose (90 mg/kg-day) including clinical signs (piloerection, ptyalism,
hunched posture, and aggressive behavior often associated with hypersensitivity to touch) and
histopathological lesions (thyroid and uterus lesions in females and lung lesions in males and
females).
ECHA (2020k. 202(h)
A one-generation reproduction/developmental exposure study in rats (summarized in two
reports from the registrant) is available on the ECHA website that evaluates the effects of
HQ-1 15 (EC )20h, y). Ten-week-old male and 9-week-old female Sprague-Dawley rats
were administered 0, 15, 30, or 60 mg/kg-day HQ-115 via daily gavage. Ten males per group
were dosed for at least 28 days (for 2 weeks before mating and for up to 2 weeks during mating)
and were euthanized after mating. Ten females per group were also dosed for 2 weeks before
mating, during mating, and continued until lactational day 4. The study was conducted according
to OECD and GLP guidelines and evaluated parental mortality, clinical signs, body weights,
food intake, organ weights (epididymides and testes), gross pathology, histopathology
(epididymides, mammary glands, ovaries, prostate, seminal vesicles, testes, uterus, and vagina),
reproductive parameters (pre-coital time, fertility and gestation indexes, post implantation loss,
number of corpora lutea and implantation sites), and developmental effects including live birth
index, number of stillborn pups, litter size, sex ratio, pup mortality, clinical signs, body weight,
body weight gain, and malformations (including a soft tissue examination with detailed
examination of the heart and great vessels). The original source studies were not available,
resulting in a low confidence rating based on deficiencies in several study evaluation domains
(Figure 2), including the lack of details on methods of endpoint assessment and presentation of
results in the available ECHA study summaries. Some concerns were raised regarding methods
used for evaluating subjective measures such as pup malformations, histopathology, and
reproductive performance, since no specific information was provided. Additionally, most data
were provided qualitatively, and the data that were provided quantitatively (mortality, clinical
signs and histopathology) did not include statistical analyses. Furthermore, number of corpora
lutea and implantation sites were not reported in the results.
Mortalities were reported for both parental males and females in the two highest dose
groups, with one male in the 30 mg/kg-day group found dead on day 27 and one male in the 60
mg/kg-day group euthanized moribund on day 2. Four females were euthanized in the 30 mg/kg-
day group, because one did not deliver and three had dead litters. No females in the 60 mg/kg-
day group survived until scheduled termination; one was found dead, and nine were euthanized
(two did not deliver, two were found moribund, and five had dead litters).
17
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
In the parental males, body weight was decreased (4.6%, p < 0.01) in the 60 mg/kg-day
group on day 8 of dosing, and body weight gain was 38% decreased (p < 0.05) during the first
week of dosing. In parental females, there were no effects on body weights during the pre-mating
and gestation periods. Body weight and body weight change were both decreased in the 15 and
30 mg/kg-d groups during lactation in a dose-related manner, but the decrease was only
statistically significant for body weight change at 15 mg/kg-day (38% ,p<0 .05). Body weight
was unchanged in the 60 mg/kg-day group, but this was reported to be due to a large variance in
this group. Mean food consumption in females was decreased (p < 0.01) from 15 mg/kg-day
during lactation, but not pre-mating or during gestation. Mean food consumption in males
decreased in the first week of treatment of >15 mg/kg-day and returned towards controls in
subsequent weeks (data not reported).
There were no clinical signs of toxicity observed in the 15 mg/kg-day group. Clinical
signs of toxicity occurred in both males and females in the 60 mg/kg-day groups, including
tremors, clonic contraction, convulsions, tonic contraction, hypoactivity, prostration, decrease in
grasping reflex, locomotory difficulties and/or hypersensitivity to the touch (incidence not
reported). Tremors, convulsions, and tonic contraction were also observed in one male in the 30
mg/kg-day group. No exposure-related effects were reported for organ weights, gross pathology,
or histopathology (no other details were provided).
Reproductive parameters were affected in parental females exposed to HQ-115, although
few details were provided. In the 60 mg/kg-day group, the mean pre-coital time (mean number of
days taken to mate) was slightly increased due to one female which mated after 13 days and was
noted to be "blocked in diestrus for several days" (data not reported). A lower number of
pregnancies was observed at 30 and 60 mg/kg-day (9/10 and 8/10 compared to 10/10 in control
and the 15 mg/kg-day group), fertility and gestation indices decreased (data not reported), and
post-implantation loss increased (153%) at the highest dose (60 mg/kg-day). Alterations in
indicators of estrus cyclicity compared to controls were observed in females exposed to 60
mg/kg-day, including increased incidence and severity of ovarian follicle development in
unscheduled dead, or surviving females (data not reported). Basophilic corpora lutea were
observed in 3/10 females and oocytes in the lumen of oviducts were observed in 2/10 females.
These changes suggest possible effects on estrous cyclicity, although an evaluation of cycle stage
was not conducted. Few females in the high-dose group delivered (number not reported), and all
their pups were found dead in the first four days after birth. There were no effects observed in
the live birth index or number of stillborn pups (data not reported). The mean number of pups per
litter was comparable in the low- and mid-dose groups compared to controls (14.1, 15.2 and
13.3. for the control, low-dose, and mid-dose groups), as well as the number of male and female
pups per litter (data not reported).
Pup mortality, clinical signs, body weight, and malformations were assessed until
postnatal day (PND) 5. The percentage of pups found dead was increased in a dose-dependent
manner in all dose groups, and deaths mostly occurred on PNDs 1 and 2 (data not reported).
Decreases in mean pup body weight and body weight gain were also observed in all dosed
groups in comparison to the control group on PNDs 1 and 5 (data not reported). The viability
index on PND4 was also reduced in all dosed groups, with no pups in the 60 mg/kg-day group
surviving, 47.5% in the 30 mg/kg-day group surviving, 19.6% in the 15 mg/kg-day group
surviving, and 95.7% in the control group surviving until PND 4 (see Figure 7). There was a
18
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
dose-related increase in the number of litters with pups with absence of milk in the stomach
observed in all dose groups (data not reported). At necropsy on PND 5, there were no exposure-
related findings from the soft tissue evaluation with detailed examination of the heart and
cardiovascular system (no other details were provided).
Study Name Study Design Animal Description Kndpoint Name Dose
(mg/kg-day)
jjlRewnn
HQ-115 F1 Viability
KCIIA 2020, mm*. mmi I-(feneration Oral Fi Rat. Sprajae-Dawiey 15 mg/kg-day and increased mortality and clinical
signs of toxicity in parental male and female rats at > 30 mg/kg-day. Developmental effects
included increased pup mortality on PND 1 and 2, decreased pup body weight/body weight gain
on PND 1 and 5, decreased viability index on PND 4 and gross pathological examination
observations in dead pups (absence of milk in the stomach) at > 15 mg/kg-day. Effects on
reproduction were observed primarily at the highest dose (60 mg/kg-day), involving decreases in
number of pregnancies and fertility and gestational indexes, possible changes in the estrous
cycle, and increases in pre-coital time and implantation loss.
19
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Other Data
Available data that provide supporting information for the evaluation of potential health
effects following exposure or treatment to HQ-115 consist of genotoxicity studies, short-term
and acute oral exposure studies, and non-oral/inhalation studies. These include one 7-day range
finding study (Huntingdon Research Center, 1992b), three acute studies (EC! 20e, f, g; 3M,
1988), eight genotoxicity studies (see Table 2 for more details), and thirteen non-oral/inhalation
studies (i.e. three evaluated toxicity of HQ-115 after a single dermal dose, three evaluated skin
irritation/corrosion, three evaluated skin sensitization, and four evaluated ocular irritation; see
Table 3 for more details).
Genotoxicity Data
Genotoxicity studies conducted on HQ-115 include four studies that used the Ames test
and a fifth study that used the mammalian cell gene mutation assay to evaluate mutagenicity.
Three chromosomal aberration (CA) studies were also available. Results from these studies are
listed in Table 2.
For the four Ames test studies, various strains of Salmonella typhimurium and
Escherichia coli were exposed to concentrations ranging from 21 to 10,000 |ig/plate for two to
three days, with and without S-9 activation (EC] 20m, 2, fl; Huntingdon Research Center.
1992a). In all four studies, HQ-1 15 was not found to have potential for mutagenicity in these
bacterial systems. A fifth study assessed the mutagenicity of HQ-115 in mouse lymphoma
L5 178 Y cells (ECHA. 2020o). Mouse lymphoma L5 178 Y cells were exposed to concentrations
of HQ-115 ranging from 0.63 to 10 mM for 3 hours or 0.16 to 7.5 mM for 24 hours without
activation or 0.63 to 10 mM for 3 hours with S-9 activation. HQ-115 did not show any
mutagenic activity in this mammalian cell system.
The ability for HQ-115 to cause CAs was tested in vitro in two studies using human
lymphocytes (ECHA. 2020n; Huntingdon Research Center. 1993c) and in a study using Chinese
hamster lung fibroblasts (Huntingdon Research Center. 1993b). One study exposed human
lymphocytes to concentrations of 156, 625, or 1,250 |ag/m L for 18 or 32 hours without S-9
activation, or to concentrations of 625, 2,500, or 5,000 |ag/m L for 18 or 32 hours with S-9
activation (Huntingdon Research Center. 1993c). The second study exposed human lymphocytes
to concentrations ranging from 2.5 to 10 mM, with and without activation, for 3, 20, or 44 hours
(ECHA. 2020n). In both studies, the proportion of aberrant cells was not significantly increased
in any of the exposure conditions in comparison to the solvent control, demonstrating that
HQ-115 did not have clastogenic activity in this in vitro system.
A CA study was also conducted in Chinese hamster lung fibroblasts (Huntingdon
Research Center, 1993b). Chinese hamster lung fibroblasts were exposed to concentrations of
1,250, 2,500, or 5,000 |ig/mL HQ-115 for 6 hours with cell collection 18 hours later, with and
without S-9 activation. Chinese hamster lung fibroblasts were also exposed to concentrations of
625, 1,250, or 2,500 |ig/mL HQ-115 for 24 hours with an immediate cell collection, without S-9
activation, and to concentrations of 1,250, 2,000, or 3,500 |ag/mL HQ-115 for 48 hours with an
immediate cell collection, without S-9 activation. In the presence of S-9 activation, a significant
increase in the proportion of aberrant cells was observed in cells exposed to 5,000 jag/m L
HQ-115 for 6 hours. Without S-9 activation, a significant increase in the proportion of aberrant
20
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
cells was observed in cells exposed to all three concentrations analyzed (>1,250 (ag/mL) for 6
hours, 2,500 |ag/m L for 24 hours, and >2,000 |ag/m L for 48 hours. Additionally, in cells exposed
to 3,500 |ig/mL for 48 hours without activation, a significant increase in the proportion of
polyploidy cells was also observed. These results demonstrate that HQ-115 does have the
potential for both clastogenic activity and polyploidy-inducing activity in this in vitro system.
21
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table 2. Summary of HQ-115 Genotoxicity Data
Endpoint
Test System
Concentrations Tested
Results Without
Activation
Results With
External
Activation
Comments
References
In vitro xciwlo.xicily studies in prokuryolic organisms
Ames Assay
(Revertant
colonies)
Salmonella
typhimurium (TA 98,
100, 1535, 1537, 1538),
Escherichia Coli (WP2
uvrA)
0, 312.5,625, 1,250,
2,500, 5,000 ng/plate for 3
days with and without
activation.
Negative
Negative
No evidence ol
mutagenicity.
ii Researc s >
Center f 1992a)
Ames Assay
(Revertant
colonies)
Salmonella
typhimurium (TA 98,
100, 102, 1535, 1537),
Escherichia Coli (WP2
uvrA)
0, 312.5,625, 1,250,
2,500, 5,000 ng/plate for
48 to 72 hours with and
without activation.
Negative
Negative
No evidence of
mutagenicity.
ECHA f2020m)
Ames Assay
(Revertant
colonies)
Salmonella
typhimurium (TA 98,
100)
0,21,62, 185, 556, 1,667
Hg/plate for 3 days with
and without activation.
Negative
Negative
No evidence of
mutagenicity.
ECHA f2020d)
Ames Assay
(Revertant
colonies)
Salmonella
typhimurium (TA 98,
100, 1535, 1537, 1538)
0, 333, 667, 1,000, 3,330,
6,670, 10,000 ng/plate for
48 hours with and without
activation.
Negative
Negative
No evidence of
mutagenicity.
ECHA (2020a)
22
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Endpoint
Test System
Concentrations Tested
Results Without
Activation
Results With
External
Activation
Comments
References
III vitro xciwlo.xicily studies in iiimiiiiitilitiii cells
Mammali;in
Cell Gene
Mutation
Mouse l\ mphoiiin
L5178Y cells
ii. () 1,250
Hg/mL for >6 hours.
Increase in the proportion
of polyploidy cells at
3,500 |ig/mL for 48 hours.
Increase in the
proportion of
aberrant cells at
5,000 ng/mL for 6
hours.
Evidence of
clastogenic and
polyploidy-
inducing
activity.
Huntingdon Research
Center f 1993b)
23
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Supporting Animal Toxicity Studies
Other studies identified for HQ-115 included one 7-day range finding study via the oral
route with limited utility for informing potential health effects after repeat-dose exposure and
three acute studies that assess the toxicity of HQ-115 after a single oral dose. Additionally, three
studies that evaluate the toxicity of HQ-115 after a single dermal dose, three studies that evaluate
skin irritation/corrosion, three studies assess skin sensitization, and four studies that assess ocular
irritation were identified. Data from these studies are summarized below and additional details
regarding methods and results are listed in Table 3.
Short-term (7-day range finding study)
Huntingdon Research Center (1992b)
Male and female 5-week-old Crl: CD (Sprague-Dawley) BR VAF Plus rats (3/group)
were dosed with 0, 10, 30, 50, or 100 mg/kg-day HQ-115 via oral gavage for up to 7 days
(Huntingdon Research Center. 1992b). The study was conducted in compliance with GLP
standards and evaluated clinical signs, body weights, food intake, organ weights (liver, kidneys,
and spleen), and gross pathology. Study confidence was not evaluated since this was a
dose-range finding study conducted for only 7 days.
Food consumption was slightly reduced in the females dosed with 50 mg/kg-day HQ-115
and was reduced in both males and females in the 100 mg/kg-day groups. Body weight gains of
males and females in the 100 mg/kg-day groups were also lower than controls. There were no
mortalities in any of the groups; however, the animals receiving 100 mg/kg-day were sacrificed
after the second day of exposure due to severe clinical signs of toxicity. No signs of toxicity were
observed in the 10 or 30 mg/kg-day groups. In males and females in the 50 mg/kg-day group,
clinical signs of toxicity included high stepping gait, piloerection, and hypersensitivity. In the
100 mg/kg-day group, clinical signs included piloerection, hunched posture, abnormal gait,
pallor to the extremities, body tremors, lethargy, and loose feces.
Absolute liver weights increased 14-16% at > 30 mg/kg-day in males and 8-19% at
> 30 mg/kg-day in females. There were no changes in spleen or kidney weights and no exposure-
related macroscopic findings at necropsy. Due to severe clinical signs of toxicity observed at
100 mg/kg-day, a high dose of 60 mg/kg-day was set for the 28-day exposure study (Huntingdon
Research Center. 1993a).
Acute Oral Toxicity
There are three single-dose studies available that evaluate the toxicity of HQ-115 after
oral exposure in rats (ECHA. 2020e. f, g; 3M. 1988). In one study, five male and five female
Sprague-Dawley rats per group were dosed with 50, 500, or 5,000 mg/kg HQ-115 via oral
gavage (EC 1 2Of; 3M, 1988). In the 50 mg/kg group, all animals survived; one animal had
diarrhea, and one animal had an enlarged pelvis in the right kidney upon necropsy. No other
clinical signs, changes in body weight gain, or gross pathological abnormalities were noted. In
the 500 mg/kg group, clinical signs of toxicity included subconvulsive jerking, prostration,
dyspnea, hypoactivity, ataxia, stained fur of the face and genitals, and hypersensitivity. Nine of
the ten animals died. At necropsy, red areas in the glandular mucosa of the stomach and nasal
discharge were noted. In the 5,000 mg/kg group, all the animals died within 15 minutes of dose
24
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
administration, and necropsy revealed diffusely light testes, red areas in the glandular mucosa of
the stomach, tan kidneys, and nasal discharge. The acute oral median lethal dose (LD50) of
HQ-115 was calculated by the study authors to be 160 mg/kg (95% confidence interval
40-560 mg/kg) for male Sprague-Dawley rats and 210 mg/kg (95% confidence interval
50-870 mg/kg) for female Sprague-Dawley rats.
A second study dosed three male and three female Sprague-Dawley rats per group with
either 25 or 200 mg/kg HQ-115 (ECUA. 2020e). In the 25 mg/kg group, all animals survived,
after that dyspnea and piloerection were noted in all males one hour after treatment. In the
200 mg/kg group, 2/3 males died within 4 hours and 15 minutes of exposure, but all females
survived. Clinical signs of toxicity included hypoactivity followed by sedation, dyspnea,
tonic-clonic convulsions, hypersalivation, and piloerection. No changes in body weight gain or
gross pathology were noted. The acute oral LD50 of HQ-115 was estimated by the study authors
to be > 200 mg/kg for male and female Sprague-Dawley rats, combined.
The third study dosed three female Wistar rats with 200 mg/kg (ECHA. 2020e). One
animal was found dead on the day of dosing. Clinical signs of toxicity included sluggishness,
blepharospasm, convulsions, pallor, and coma. No changes in body weight gain were noted. The
acute oral LD50 of HQ-115 was estimated by the study authors to be > 200 mg/kg for female
Wistar rats.
Acute Dermal Toxicity
There are three studies available that evaluate the systemic toxicity of HQ-115 after a
single dermal administration of HQ-1 15 (ECHA, 2020b, c, d). In one study, five male and five
female New Zealand White (NZW) rabbits were dermally administered 200, 350, 500, or
2,000 mg/kg HQ-1 15 (ECI 20b). All animals survived in the 200 mg/kg group, while 2/5
males and 0/5 females died in the 350 mg/kg group, and all animals died in the two highest dose
groups. All mortality occurred within two days of dosing. Clinical signs of toxicity included
hypoactivity, loss of appetite, staggered gait, subconvulsive jerking, miosis, excessive salivation,
aggressive behavior, tremors, prostration, shallow breathing, and clonic convulsions. No effects
on body weight were observed. Slight to severe erythema, slight edema and desquamation,
subcutaneous hemorrhaging, and possible necrosis were observed at the site of application, but
no other changes in gross pathology were noted. The acute dermal LD50 of HQ-115 was
calculated by the study authors to be 371 mg/kg (95% confidence interval 254-542 mg/kg) for
male NZW rabbits and 418 mg/kg (95% confidence interval 329-486 mg/kg) for female NZW
rabbits.
In a second study, five male and five female Sprague-Dawley rats were dermally
administered 2,000 mg/kg HQ-1 15 (ECHA, 2020c). All animals survived and no clinical signs
were noted; however, a reduction in body weight gain or slight body weight loss was observed in
3/5 females over the 14-day observation period. No cutaneous reactions or changes in gross
pathology were observed. The acute dermal LD50 of HQ-115 was estimated by the study authors
to be > 2,000 mg/kg for male and female Sprague-Dawley rats.
In the third study, male and female animals were dermally administered HQ-115 under
occlusive conditions, and an LD50 was determined (EC )20d). However, no details were
25
-------
Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
available for the species, number of animals, or doses applied. The acute dermal LD50 of HQ-
115 was calculated by the study authors to be 400 mg/kg (95% confidence interval 329-486
mg/kg) for males and females.
Acute Skin Irritation/Corrosion
Three studies are available that evaluate the ability for HQ-115 to cause skin irritation
and corrosion in NZW rabbits (ECHA, 2020s. t, u). Reversible erythema and no edema were noted
in one study using only one female rabbit (ECHA, 2020u). and very slight to severe erythema with
slight edema was noted in a second study, which used three male rabbits (ECHA, 2020t). In the
third study, irreversible erythema with necrosis and irreversible edema were observed in 3/3
rabbits, and the study concluded that HQ-1 15 is corrosive to the skin (ECHA, 2020s; 3M, 1988).
Skin Sensitization
Three studies are available that evaluate the ability for HQ-115 to cause skin sensitization
in guinea pigs (ECHA. 2020v. w, x). Two studies found no evidence of skin sensitization
(ECHA. 2Q20w. x); although one of those studies noted slight skin irritation following the
intradermal injection of HQ-115, no response was noted after the initial or challenge dermal
applications ( O20w). The third study noted discrete to severe erythema, dryness of the
skin, edema and/or brownish discoloration of the skin in 19/20 animals after the first challenge
with 50% HQ-115, but these effects were only seen in 1/20 animals after a second challenge with
10% HQ-1 15 (ECHA. 2020v). The study authors concluded that HQ-1 15 induced delayed
contact hypersensitivity in only 5% of guinea pigs.
Ocular Irritation
Four studies are available that assess the ability of HQ-115 to cause ocular irritation
(ECHA. 2020k. 1). One study was an ex vivo study in chicken eyes (ECHA. 20201). After 10
seconds of exposure to 30 mg of HQ-115, corneal swelling, severe corneal opacity, and severe
fluorescein retention indicating epithelial cell damage were observed.
Two studies assessed ocular irritation in NZW rabbits following in vivo exposure to
HQ-1 15 for 72 hours (ECHA. 2020i. k; 3M. 1988). In one study, the eyes of three NZW rabbits
were exposed to 90 mg of HQ-115 for 72 hours and observed for irritation for 21 days after
exposure (ECHA. 2020k; 3M. 1988). Irreversible corneal opacity and epithelial peeling, iris
effects, conjunctival lesions, and chemosis were observed. In the second study, the left eyes of
three male NZW rabbits were exposed to 100 mg of HQ-115 for 72 hours and observed for
irritation for 22 days after exposure. Very slight to marked chemosis and redness of the
conjunctiva were noted, along with a clear to whiteish purulent discharge; some of these effects
persisted to the end of the observation period in 2/3 rabbits. Reversible discoloration in the
conjunctivae was also observed in two animals, and reversible slight iritis and corneal opacities
were observed in all animals.
26
-------
Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
In a fourth study, HQ-115 was applied to the eyes of three animals; however, information
on the sex, species, dose, and duration of the study was not provided (ECUA. 2020i). HQ-1 15
was found to cause irritation of the conjunctivae, with a mean score of 3/3; chemosis, with a
mean score of 3.3/4; corneal opacity, with a mean score of 2-3.3/4; and iris effects, with a mean
score of 1/2.
27
-------
Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table 3. Other Supporting Animal Toxicity Studies
Test Type
Materials and Methods
Results
References
Short-term
Short-term range
finding
Male and female 5-week-old Crl: CD (Sprague
Dawley) BR VAF Plus rats (3/group) were dosed with
0, 10, 30, 50, or 100 mg/kg-day HQ 115 via oral
gavage for up to 7 days. The study was conducted in
compliance with Good Laboratory Practice (GLP)
standards (EPA and OECD) and evaluated clinical
signs, body weights, food intake, organ weights (liver,
kidneys, and spleen), and gross pathology.
Food consumption was reduced in the females > 50
mg/kg-day and reduced in males at 100 mg/kg-day.
Body weight gains reduced in males and females at 100
mg/kg-day. Clinical signs observed at >50 mg/kg-day.
Rats at 100 mg/kg-day were sacrificed after the second
day of exposure due to severe clinical signs of toxicity.
Absolute liver weights increased 14-16% at > 30
mg/kg-day in males and 8-19% at > 30 mg/kg-day in
females. Due to severe clinical signs of toxicity
observed at 100 mg/kg-day, a high dose of 60 mg/kg-
day was set for the 28-day exposure study.
ECHA (2020f):
Huntingdon Research
Center (1992b): 3M
(1988)
Morltilily Jollon-iiifi acute oral and dermal exposure
Acute oral
mortality
Male and female Sprague-Dawley rats (5/sex/group)
were dosed with 50, 500, or 5,000 mg/kg HQ-115. Rats
were assessed for mortality, clinical signs, and body
weight gain over a period of 2 weeks, and a
macroscopic necropsy was performed.
Mortality at >500 mg/kg; clinical signs at 500 mg/kg
including clonic convulsions, hypoactivity, and
hypersensitivity to touch.
Red glandular mucosa of the stomach, nasal discharge,
and discoloration of the testes and kidneys. Oral LD50
in males: 160 mg/kg (95% CI 40-560 mg/kg); Oral
LD50 in females: 210 mg/kg (95% CI: 50-870 mg/kg).
ECHA (2020:0: 3M
(1988)
Acute oral
mortality
Male and female Sprague-Dawley rats (3/sex/group)
were dosed with 25 or 200 mg/kg HQ-115. Rats were
assessed for mortality, clinical signs, and body weight
gain over a period of 2 weeks, and a macroscopic
necropsy was performed.
Mortality at 200 mg/kg; clinical signs at 20 mg/kg
including dyspnea and piloerection in 3/3 males; clinical
signs at 200 mg/kg including dyspnea, piloerection,
hypoactivity and sedation, tonic-clonic convulsions, and
hypersalivation in all animals. Oral LD50 > 200 mg/kg.
ECHA (2020e)
Acute oral
mortality
Three female Wistar rats were dosed with 200 mg/kg
HQ-115. Rats were assessed for mortality, clinical
signs, and body weight at an unspecified timepoint.
Mortality; clinical signs including sluggishness,
blepharospasm, convulsions, pallor, and/or coma. Oral
LD50 > 200 mg/kg.
ECHA (2020e)
28
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Acute dermal
toxicity
Male and female NZW rabbits (5/group) were dermally
dosed with 200, 350, 500, or 2,000 mg/kg HQ-115
under semi-occlusive conditions. Mortality, clinical
signs, body weight, and dermal reactions were assessed
over a 2-week observation period, and a macroscopic
necropsy was performed.
Mortality at >350 mg/kg; clinical signs including
hypoactivity, loss of appetite, staggered gait,
subconvulsive jerking, miosis, excessive salivation,
aggressive behavior, tremors, prostration, shallow
breathing, and clonic convulsions. Slight to severe
erythema, slight edema and desquamation, subcutaneous
hemorrhaging, and possible necrosis. Dermal LD50 in
males: 371 mg/kg (95% CI 254-542 mg/kg); Dermal
LD50 in females: 418 mg/kg (95% CI: 329^186 mg/kg).
ECHA (2020b)
Acute dermal
toxicity
Male and female Sprague-Dawley rats (5/sex) were
dermally dosed with 2,000 mg/kg HQ-115 under semi-
occlusive conditions. Mortality, clinical signs, body
weight, and dermal reactions were assessed over a
2-week observation period, and a macroscopic
necropsy was performed.
Reduced body weight gain or slight body weight loss.
Dermal LD50 in males and females > 2,000 mg/kg.
ECHA (2020c)
Acute dermal
toxicity
Test material was applied under occlusive coverage and
LD50 was determined in male and female animals
(species and number not specified)
Dermal LD50 in males and females: 400 mg/kg (95%
CI: 329-486). No details of the results or observations
were reported.
ECHA (2020d)
Oilier health ejjecls Jo/lou-iiifi derma! or ocular exposure
Skin irritation/
corrosion
Three NZW rabbits (sex not specified) were dermally
dosed with 0.5 mL HQ-115 for 4 hours under semi-
occlusive conditions, and the degrees of erythema and
edema were assessed using the Draize technique over a
2-week observation period.
Irreversible erythema with necrosis: mean score of 3/4;
irreversible edema: mean score of 2.33/4.
ECHA (2020s): 3M
(1988)
Skin irritation/
corrosion
Three male NZW rabbits were dermally dosed with
500 mg HQ-115 for 4 hours under semi-occlusive
conditions, and dermal irritation was evaluated over a
period of 2 weeks.
Very slight to severe erythema (grades 1-4), slight
edema (grade 2), and skin dryness.
ECHA (20201)
Skin irritation/
corrosion
One female NZW rabbit was dermally dosed with
500 mg HQ-115 for 4 hours under semi-occlusive
conditions, and the degrees of erythema and edema
were assessed daily for 3 days using the Draize
technique.
Reversible erythema: mean score of 0.66/4; edema:
mean score of 0/4.
ECHA (2020u)
29
-------
Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Skin sensitization
Male and female Hartley guinea pigs (10/sex) were
intradermally injected with 0.1% w/w HQ-115 in saline
and cutaneously dosed with 50% HQ-115 on day 8 and
challenged on day 22 with a cutaneous dose of 50%
HQ-115 in saline and again on day 40 with 10%
HQ-115 in saline. Animals were assessed for cutaneous
reactions, clinical signs, and body weight.
Discrete to severe erythema, dryness of the skin, edema
and/or brownish discoloration were observed in 19/20
animals after the first challenge with 50% HQ-115.
Discrete erythema, dryness of skin, and brownish area
was observed in 1/20 animals after the second challenge
with 10% HQ-115. No clinical signs of toxicity or
changes in body weight gain were noted.
ECHA (2020V)
Skin sensitization
Female Dunkin-Hartley guinea pigs (10/group) were
intradermally injected with 0.5% w/w HQ-115 in water
and cutaneously dosed with 20% HQ-115 in water and
challenged again after two weeks with a cutaneous
dose of either 5% or 10% HQ-115 in water. Animals
were assessed for cutaneous reactions, clinical signs,
and body weight.
Slight skin irritation following intradermal injection. No
dermal responses following the initial topical application
or the challenge application.
ECHA (2020w)
Skin sensitization
Five male Dunkin-Hartley guinea pigs were
intradermally injected with 0.3% w/w HQ-115 in corn
oil, cutaneously dosed with 10% HQ-115 in corn oil
one week later and challenged two weeks later with a
cutaneous dose of 3% HQ-115 in corn oil. Animals
were assessed for cutaneous reactions.
No effects noted.
ECHA (2020x)
Ocular irritation
Ex vivo chicken eyes were exposed to 30 mg HQ-115
for 10 seconds and assessed for corneal effects such as
swelling, opacity, and fluorescein retention by
damaged epithelial cells.
Increased corneal thickness, severe corneal opacity, and
severe fluorescein retention.
ECHA (20201)
Ocular irritation
Three male NZW rabbits were ocularly administered
100 mg HQ-115 for 72 hours, and the degree of ocular
irritation was assessed over a period of 22 days.
Very slight to marked chemosis (grades 1 to 3), very
slight to marked redness of the conjunctiva (grades 1 to
3) and a clear to whiteish purulent discharge;
irreversible in 2/3 animals. Reversible brownish or
whiteish area in the conjunctivae in 2/3 animals;
reversible slight iritis (grade 1), reversible slight corneal
opacity (grade 1 or 2).
ECHA (2020i)
Ocular irritation
Three NZW rabbits (sex not specified) were ocularly
administered 90 mg HQ-115 for 7 hours, and the
degree of ocular irritation was assessed using the
Draize technique over a period of 3 weeks.
Irreversible corneal opacity: mean score of 2-3/4;
irreversible iris effects: mean score of 1/2; irreversible
conjunctival lesions: mean score of 3/3; irreversible
chemosis: mean score of 3-4/4.
ECHA (2020k); 3M
(1988)
30
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Ocular irritation
HQ-115 was applied to the eyes of three animals (sex,
species and duration not specified) and ocular irritation
was scored for conjunctivae, chemosis, corneal opacity,
and iris.
Conjunctivae: mean score of 3/3; chemosis: mean score
of 3.3/4; corneal opacity: mean score of 2-3.3/4; iris:
mean score of 1/1.
ECHA (2020i)
LD50 = median lethal dose; CI = confidence interval
31
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
DERIVATION OF REFERENCE VALUES
The hazard and dose-response database for repeated exposure to HQ-115 is limited to
studies via the oral route of exposure. There are no known inhalation studies for HQ-115.
Several dermal studies were identified in which acute toxicity, skin irritation, and sensitivity to
HQ-115 were evaluated in rabbits, rats, or guinea pigs (see Table 3). In general, HQ-115 caused
slight to severe skin effects (e.g., erythema, edema, necrotic lesions) with a dermal LD50 across
species and sexes tested of approximately > 350 mg/kg. HQ-115 was also identified as an ocular
irritant in rabbit and chicken eyes. No known studies have evaluated potential cancer effects of
HQ-115 by any exposure route; however, several studies relevant to potential
mutagenic/clastogenic cancer mechanism(s) were overwhelmingly negative. The purpose of this
assessment is to inform human health hazard(s) associated with chronic duration/lifetime
exposures to HQ-115. Therefore, only a noncancer chronic reference dose (RfD) is derived in
this assessment for the oral route of exposure. The RfD derived in this assessment is an estimate
of an oral exposure to the human population (including susceptible subgroups and lifestages)
likely to be without an appreciable risk of adverse health effects over a lifetime.
Derivation of Oral Reference Dose
No human epidemiological studies were identified for HQ-115. The repeated exposure
oral route hazard and dose-response evidence base for HQ-115 is limited to one high confidence
28-day study (Huntingdon Research Cem 3a), a low confidence 29-day study (ECH.A.
2020r), and a low confidence one-generation reproductive/developmental study (EC. 20h.
y), all in SD rats. The 29-day and reproductive/developmental rat studies were available on the
ECHA website only (original source studies were not available); as such, there were limitations
in reporting of methods and results that resulted in the low confidence rating. However, the
information from all three rat studies was deemed useful for informing health hazards following
HQ-115 oral exposure(s) and were considered in the identification of candidate critical effects
and PODs, and subsequent toxicity value derivation.
The 28-day (Huntingdon Research Center. 1993a). 29-day (EC )20f) and one-
generation (ECI 20h. y) rat studies were all reported to be conducted according to OECD
guideline protocol and under GLP conditions. For all three studies, low, but adequate numbers of
animals (n = 5-10) were tested across multiple dose groupings (ranging from 1.67-90 mg/kg-
day) and involved the comprehensive evaluation of in-life health status, and blood/serum
parameters, organ weights, gross pathology, and histopathology upon necropsy (sqq Animal
Studies section). In the 28 and 29-day oral studies, the liver was consistently affected by oral
HQ-115 exposure. This included increases in absolute and relative liver weights, gross
enlargement of the liver, increased incidence of hepatocyte hypertrophy and/or vacuolation, and
serum biomarkers indicative of hepatocellular (e.g., ALT) and hepatic biliary epithelium (e.g.,
ALP) injury in male and female rats. It was also noted in the 28-day study that extramedullary
hematopoiesis was observed, albeit at low incidence, in the livers of HQ-115 treated male rats in
the low-dose (1.67 mg/kg-day) group and in females in the mid-dose (10 mg/kg-day) group
(Huntingdon Research Center. 1993a); this specific lesion is uncommon in adult rats and is
further evidence of hepatocyte degeneration (Cenariu et al. 2021; Yamamoto et al.. 2016;
Maronpot. 2014). According to Hall et al. (2012). this constellation of effects is consistent with
criteria supporting a determination of adverse liver effects. The dose-response data for liver
injury in the 28-day study did not identify a sex-specific sensitivity as the effects, other than
32
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
extramedullary hematopoiesis, occurred at the highest dose tested in male and female rats. In
contrast, in the ECH.A. (2020r) 29-day study, male rats appeared to be more sensitive than
females to liver injury. Increased liver weight, enlargement of the liver, and histopathological
evidence was evident at > 45 mg/kg-day in male rats; the same effects were observed only at the
highest dose tested (90 mg/kg-day) in females. Hepatic serum biomarker (e.g., ALT, AST, ALP)
and liver weight data in this study were only qualitatively reported; therefore, these endpoints
were not considered further for dose-response modeling.
Effects in the kidneys were also reported following 28 days of exposure to HQ-115,
mainly at the highest dose tested in rats (Huntingdon Research Center, 1993a). This included
increases in absolute and relative kidney weights (> 10% in males at 60 mg/kg-day), increased
BUN (males and females exposed to 60 mg/kg-day), decreased urinary pH (males and females
exposed to > 10 mg/kg-day), and increased urine volume (38% in males exposed to 60 mg/kg-
day). Other health effects were also observed in rats after 28- or 29-days of oral HQ-115
exposure (e.g., clinical signs of toxicity, spleen weights; decreased blood cholesterol) but they
generally either occurred at the highest tested dose, were sporadic, not dose-related, or were not
supported by corroborative evidence of toxicity.
Effects of concern have also been observed following repeated oral HQ-115 exposure in
a reproductive/developmental study design in rats (ECHA.. 2020h. y). Significant toxicity
occurred in parental (P0) rats at > 30 mg/kg-day including mortality (1/10 males and 4/10
females died at 30 mg/kg-day; 1/10 males and all females died at 60 mg/kg-day), and severe
clinical signs of toxicity (e.g., tremors and convulsions) in males and females at 60 mg/kg-day.
Females in the 60 mg/kg-day group also experienced significant reproductive effects (e.g., 153%
increase in post-implantation loss, absence of delivery). The developing rat fetus/neonate
appeared to be particularly sensitive to HQ-115 exposure as increased mortality (PND 1 and 2),
decreased body weight/body weight gain (PND 1 and 5), and decreased viability (PND 4) were
observed in offspring at > 15 mg/kg-day. Even at the lowest tested parental exposure dose (15
mg/kg-day), 20% of pups delivered died by PND 4 (see Figure 7) compared to 4% in the control
group.
Liver effects in adults and decreased survival of birthed offspring were identified as
potential critical effects for oral HQ-115 exposure. While the adult rats across the 28-/29-day and
single generation reproductive studies also experienced significant clinical signs of toxicity,
these effects generally occurred at the highest tested dose in each study and no corroborative
neurotoxicity evaluations were included. As such, clinical signs of toxicity are of uncertain
significance and were not considered further. Kidney effects were observed following 28 days of
exposure but were also not considered further, since these effects were observed predominantly
at the highest tested dose in a single study.
Both the HQ-115-induced liver effects, observed in male and female rats from the 28-day
(Huntingdon Research Center. 1993a) and 29-day (ECHA. 2020r) studies, and decreased
survival in postnatal rats (ECHA, 2020h, y) (see Table 4) were evaluated for amenability to
Benchmark Dose (BMD) modeling. For liver weight changes from Huntingdon Research Center
3a). relative liver weight, the preferred metric for this organ based on its proportional
relationship to body weight (Bailey et at.. 2004) was included in BMD modeling. Consistent
with the EPA's Benchmark Dose Technical Guidance ( ), the BMDs and 95%
33
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
lower confidence limit on the BMDs (BMDLs) for increased relative liver weight, serum ALP,
and incidence of hepatocyte hypertrophy were estimated using a benchmark response (BMR)
representative of a biologically and/or statistically significant level of change for continuous
(e.g., relative liver weight; serum ALP) or dichotomous (e.g., incidence of hepatocyte
hypertrophy) endpoints. For liver weight changes, a 10% increase over control is considered to
be of biological significance for this assessment. For serum ALP, a 1 standard deviation (SD)
change over control was used. For hepatocyte hypertrophy, a 10% increased incidence over
control was used. Increased hepatocyte hypertrophy in male and female rats from the
Huntingdon Research t ^itpt > study and in female rats from the ECHA (2Q20r) study was
observed only in the highest dose group; therefore, the data were not amenable for BMD
modeling. Instead, a NOAEL/LOAEL approach was used to estimate PODs for these endpoints.
For quantal endpoints such as postnatal survival, the BMD Technical Guidance states
"[bjiological considerations may warrant the use of a BMR of 5% or lower for some types of
effects (e.g., frank effects) ..." Incidences of PND4 survival were modeled by eliminating the
high dose group because the mean number of pups/litter were not provided for this group in the
ECHA. (2020h. 2020y) report (see Appendix B for more details). The data were adjusted for litter
effects using a Rao-Scott transformation. As increased treatment-related fetal mortality is
considered a frank effect, a BMR of 1% extra risk was selected for derivation of the POD to
account for the biological severity of this endpoint (i.e., mortality), consistent with prior
assessments modeling fetal mortality ( s21e).
34
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table 4. Data for Liver Effects in Adult Rats and Developmental Effect in Birthed
Offspring from Rat Toxicity Studies of HQ 115 Considered for BMDS Modeling
Huntingdon Research Center (1993a)
Dose, mg/kg-daya
0
1.67
10
60
Relative liver weight in
males- (g/100g)b
5.83 ±0.3
6 ±0.23
(+3%)
6.12 ±0.404 (+5%)
8.49 ±0.427***
(+36%)
Relative liver weight in
females- (g/100g)b
4.93 ± 0.248
5.33 ±0.721
(+8%)
5.34 ±0.519
(+8%)
7.33 ±0.781***
(+49%)
Serum ALP in males-
mU/mLb
373 ±65.98
373 ±46.5
(-1%)
350 ±66.56
(-7%)
498 ±69.93**
(+32%)
Hepatocyte hypertrophy in
males - incidence
0/5
0/5
0/5
5/5
Hepatocyte hypertrophy in
females - incidence
0/5
0/5
0/5
4/5
ECHA (2020r)
Dose, mg/kg-daya
0
15
45
90
Hepatocyte hypertrophy in
males - incidence
0/5
0/5
4/5
5/5
Hepatocyte hypertrophy in
females - incidence
0/5
0/5
0/5
4/7
ECHA (202011. 2020v)
Dose, mg/kg-day
0
15
30
60
Viability index at PND 4 (%)
95.7
79.6
47.5
0
Offspring loss at PND 4°
2.94
8.78
12.80
_d
aDosimetry: Oral rat exposures are expressed in mg/kg-day as reported by the study authors.
bValues expressed as mean ± SD. Parentheses show % change relative to control = ([treatment mean - control
mean] + control mean) x 100. Number of animals per dose group = 5.
°Viability indices reported were multiplied times total number of pups born to calculate the number of pups died at
PND 4. The data represent the PND 4 offspring loss incidence adjusted for litter effects using a Rao-Scott
transformation (see Appendix B for details).
dThe high dose group was eliminated when modeling the offspring survival data because the ECHA (2020h. 202(>v)
report did not provide the number of pups/litter in this group (see Appendix A for more details).
**Statistically (p < 0.01) significant change from control.
***Statistically (p < 0.001) significant change from control.
The results of the BMD modeling of the selected endpoints are provided in Table 5; the
full BMD methods and results are provided in Appendix B.
In Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral
Reference Dose ( ), the EPA endorses a hierarchy of approaches to derive human
equivalent oral exposures from data from laboratory animal species, with the preferred approach
being physiologically based toxicokinetic modeling. Without a complete physiologically-based
toxicokinetic model, other approaches might include using available chemical-specific
information (e.g., clearance or plasma half-life values). In the absence of chemical-specific
models or data to inform the derivation of human equivalent oral exposures, the EPA
recommends that doses be scaled allometrically using body weight (BW)3/4 as a default method
35
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
to extrapolate toxicologically equivalent doses of orally administered agents from laboratory
animals to humans for the purpose of deriving an RfD, under certain exposure conditions. More
specifically, the use of BW3 4 scaling for deriving an RfD is recommended when the observed
effects are associated with the parent compound or a stable metabolite, but not for portal-of-entry
effects. For HQ-115, there are no data available to inform cross-species kinetics between rats and
humans, as such, human equivalent dose PODs (PODhed) based on allometric scaling are
provided in Table 5.
Table 5. Candidate PODs for Derivation of the Chronic RfD for HQ-115
Endpoint
POD type
POD
mg/kg-day
PODhed3
mg/kg-day
Reference
Increased relative liver
weight in adult males
BMDLiord
14
3.4
Huntingdon Research
Center (1993a)
Increased relative liver
weight in adult females
BMDLiord
13
2.9
Huntingdon Research
Center (1.993a)
Increased serum ALP in
adult males
BMDLi sd
20
4.8
Huntingdon Research
Center (1.993a)
Increased hepatocyte
hypertrophy in adult males
NOAELb
10
2.4
Huntingdon Research
Center (1.993a)
Increased hepatocyte
hypertrophy in adult
females
NOAELb
10
2.2
Huntingdon Research
Center (1.993a)
Increased hepatocyte
hypertrophy in adult males
BMDLioer
11
2.6
ECHA (2020r)
Increased hepatocyte
hypertrophy in adult
females
NOAELb
45
9.9
ECHA (2020r)
Decreased survival of
offspring at PND 4
BMDLier
0.39°
0.086
ECHA (202011.
2020v)
a HEDs were calculated using species specific application of a dosimetric adjustment factor (DAF) as
recommended by U.S. EPA (20.1.1). The DAFs are calculated as follows: DAF = (BWa1/4 ^ BWh1/4), where
BWa = animal body weight, and BWh = human body weight. Default body weight for male adult SD rats (0.267
kg [for subchronic duration]) and for female adult SD rats (0.204 kg [for subchronic duration]) and a reference
body weight of 80 kg for humans, as recommended in 88). were used to calculate the DAFs.
bNOAEL is based on increased incidence of hepatocyte hypertrophy at highest dose compared to controls and any
other treatment group.
0 Reported means were modeled after adjusting for litter effects using a Rao-Scott transformation (Fox et at..
20.1.6) and described in Appendix B. The Rao-Scott transformation entails dividing the PND4 offspring survival
incidence by a design effect to approximate the true variance in the clustered data.
BMDL = 95% lower confidence limit on the BMD. Subscripts denote BMR: 0.1RD = dose associated with 10%
relative deviation from the control; 1SD = dose associated with 1 standard deviation relative risk from the control;
0.01ER = dose associated with 1% extra risk from the control
As illustrated in Table 5, the candidate PODheds for the constellation of liver effects from
across the 28- and 29-day repeat-dose studies in adult rats ranged from 2.2-9.9 mg/kg-day.
Increased hepatocyte hypertrophy in male and female rats (Huntingdon Research Center. 1993a)
provided the lowest liver-specific candidate PODhed at 2.2 mg/kg-day. Hepatocyte hypertrophy
represents histological evidence of altered hepatocellular architecture and is part of a pattern or
36
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
progression of chemical-induced alteration in the liver including increased overall size/mass of
the organ, and release of serum biomarkers indicative of cell destruction (e.g., ALT from
hepatocytes; ALP from biliary epithelium) (Hall et at. J ). This progressive profile of liver
injury supports identification of hepatocyte hypertrophy in male and female rats (Huntingdon
Research Center. 1993a) at 2.2 mg/kg-day as a candidate POD for derivation of a RfD. Further,
the PODheds calculated for hepatocyte hypertrophy in male rats were within an order of
magnitude across both the ECHA (2Q20r) and Huntingdon Research Cent 3a) studies.
The effects in offspring from the one-generation reproductive/developmental rat study
(ECHA, 2020h, y) were of significant concern. Specifically, a significant decrease in survival of
birthed offspring occurred at the lowest dose tested and resulted in a POD of 0.39 mg/kg-day
(PODhed of 0.086 mg/kg-day). Since effects were observed at the lowest dose tested, there is
uncertainty around what dose would be required to obtain a NOAEL for this effect. Further, the
lower bound estimate on the POD (i.e., BMDL) is below the range of the observed data (15
mg/kg-day-60 mg/kg-day). Considering the severity of this developmental effect at a PODhed
that is over an order of magnitude lower than the lowest liver effect-based PODhed in adults,
decreased survival of offspring at PND 4 was identified as a candidate critical effect, and was
further evaluated for derivation of a chronic RfD (see Table 6).
37
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table 6. Candidate Chronic Reference Doses for HQ-115
Endpoint
PODhed
mg/kg-
day
UFh
UFa
UFs
UFl
UFd
UFca
Candidate RfD
(mg/kg-day)
Increased hepatocyte
hypertrophy in adult
males and females
(Huntingdon Research
Center. 1993a)
2.2
10
3
10
1
10
3,000
7 x 10"4
Decreased survival of
offspring at PND 4
(ECHA. 202011. v)
0.086
10
3
1
1
10
300
3 x 10"4
aUFc = composite uncertainty factor; the multiplicative product of the individual uncertainty factors.
Selection of the Chronic Reference Dose
Under EPA's A Review of the Reference Dose and Reference Concentration Processes
( 4. 2002) and Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry (U.S. EPA. .1.994). five possible areas of uncertainty and
variability were considered in deriving the chronic RfD for HQ-115. Application of uncertainty
factors (UF) across the two candidate critical effects revealed greater quantitative uncertainty
associated with the hepatocyte hypertrophy effect and POD; a composite UF of 3,000 was
identified for hepatocyte hypertrophy in adults whereas for offspring survival, a composite UF of
300 was applied (see Table 6). The distinction between the two candidate effects is that a
subchronic-to-chronic duration UF (UFs) of 10 was applied to the hepatic PODhed in adults as
the study was 29 days in duration. For reduced offspring survival, a UFs of 1 was applied since
the developmental period, particularly in utero development, is recognized as a susceptible
lifestage that may confer effects on an exposed individual or population over the course of a
lifetime ( ). As demonstrated in Table 6, the lower RfD of 3 x 10"4 mg/kg-day
based on decreased survival of offspring is selected as the chronic RfD for HQ-115. Further, as
TFSI is the desalted form of HQ-115 in aqueous environments, the RfD is also applicable to
TFSI. Table 7 summarizes the uncertainty factors for the chronic RfD for HQ-115. Confidence in
the chronic RfD for HQ-115 is low, as described in Table 8. The low confidence in the chronic
RfD resulting from deficiencies in the principal study, quantitation of the PODhed and database
indicate a high level of uncertainty in the derived RfD. Nevertheless, this RfD may be useful for
some decision purposes (U.S. EPA. 2005).
38
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table 7. Uncertainty Factors for the Chronic RfD for HQ-115 (CASRN 90076-65-6)
UF
Value
Justification
UFa
3
A UFa of 3 is applied to account for uncertainty in characterizing the toxicokinetic and toxicodynamic
differences between animals and humans following oral HQ-115 exposure. Cross-species dosimetric
adjustment (HED calculation) between rats and humans was performed using allometric scaling (U.S.
EPA. 2011). accounting for some aspects of the cross-species toxicokinetic processes. The application
of a 3 represents residual toxicokinetic uncertainty and potential toxicodynamic differences across
species.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The database for
repeated oral exposures to HQ-115 is limited to a 28-d, 29-d, and one-generation
reproductive/developmental study, all in rats. There is no longer-duration repeat-dose studies, or,
multi-generational reproductive/developmental toxicity studies, available following oral exposure.
UFh
10
A UFh of 10 is applied to account for interindividual variability in the susceptibility of the human
population because of both intrinsic and extrinsic factors that can influence the response to dose, in the
absence of chemical-specific information to assess toxicokinetic and toxicodynamic variability of HQ-
115 in humans.
UFl
1
A UFl of 1 is applied because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because the POD comes from a reproductive/developmental study in rats. A
developmental period is recognized as a susceptible life stage in which exposure during certain time
windows (e.g., gestational) is more relevant to the induction of developmental effects than lifetime
exposure ("U.S. EPA. 1991)
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMDL = benchmark dose lower confidence limit; HED = human equivalent dose.
POD = point of departure; RfD = reference dose; UF = uncertainty factor; UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor;
UFl = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic duration uncertainty factor.
Confidence in the chronic RfD for HQ-115 is low, as described in Table 8.
Table 8. Confidence Descriptors for the Chronic RfD for HQ 115 (CASRN 90076-
65-6)
Confidence Categories
Designation
Discussion
Confidence in study
L
Confidence in the principal study fECHA, 2020h. v) is low. The
reproductive/developmental rat study was only available as a web report
summary on the European Chemicals Agency public database, (see Figure
2 and information available on HAWC").
Confidence in database
L
Confidence in the database for HQ-115 is low. The relevant oral exposure
database consists of a 28-day, 29-day, and one-generation
reproductive/developmental studies, all in rats. No longer-duration,
repeat-dose toxicity studies are available following exposure via any
route.
Confidence in quantification
of the PODhed
L
Confidence in the quantification of the POD is low based primarily on the
estimated BMDL that is below the range of the observed data (see
Appendix B for details).
Confidence in chronic RfD
L
The overall confidence in the chronic RfD is low based on the low
confidence in the selected principal study and database deficiencies.
BMD = benchmark dose; BW = body weight; HED = human equivalent dose; POD = point of departure;
RfD = reference dose
39
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
DERIVIATION OF INHALATION REFERENCE CONCENTRATIONS
No studies have been identified that examine noncancer effects of HQ-115 via the
inhalation exposure route.
SUMMARY OF NONCANCER REFERENCE VALUES
A summary of the noncancer reference values is shown in Table 9.
Table 9. Summary of Noncancer Reference Values for HQ-115 (CASRN 90076-65-6)
Toxicity
Type(units)
Species
/Sex
Critical
Effect
Reference
Value
(mg/kg-day)
POD
Method
PODhed
(mg/kg-
day)
UFC
Principal
Study
Chronic RfD
(mg/kg-day)
Rat/M
andF
Decreased
survival of
offspring at
PND 4
3 x 10"4
BMDLier
0.086
300
ECHA
(202011.
2020v)
Chronic RfC
(mg/m3)
NDr
BMDL = benchmark dose lower confidence limit (subscripts denote benchmark response: i.e., 1ER = dose
associated with a 1% extra risk in parameter); F = females; M = male(s); NDr = not derived; PODhed = human
equivalent point of departure; RfC = reference concentration; RfD = reference dose; UFc = composite uncertainty
factor.
CARCINOGENICITY ASSESSMENT
No studies have been identified that examine potential carcinogenicity of HQ-115 via any
route of exposure.
40
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
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dossier/18080/7/7/2/?documentUUID=dae86f4a-a82c-406a-9b38-866230b2c2f4.
ECHA (European Chemicals Agency). (2020n). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Genetic toxicity: in vitro: 003 Key | Experimental
result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/1808 ocumentUUID=6433cc9d-df5a-4aa8-b89b-61d505e506df.
ECHA (European Chemicals Agency). (2020o). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Genetic toxicity: in vitro: 006 Key | Experimental
result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/1808Q/7/7/2./?documentUUID=bd0849cl-1683~4af0-bdec-7306f9cec6bb.
ECHA (European Chemicals Agency). (2020p). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Genetic toxicity: in vitro: 007 Supporting |
Experimental result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/1808o/ '/ '/ /¦ JocumentlllHD=55784324-72e4-4336-bbf7-123ea525c221.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
ECHA (European Chemicals Agency). (2020q). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Genetic toxicity: in vitro: 008 Supporting |
Experimental result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/1808 0cumentUUID=c2al8dc4-c2c2-465e-a9ff-195bb83dbcQa,
ECHA (European Chemicals Agency). (2020r). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Repeated dose toxicity: oral: 002 Key |
Experimental result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/18080/7/6/2/?documentUUID=fel90204-fa2f-48a5-bfll-74b30cle0b21.
ECHA (European Chemicals Agency). (2020s). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Skin irritation/corrosion: 001 Key | Experimental
result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/1808Q/7/4/2./?documentUUID=ecf34ffd-lalc-49c8-bb60-f52f9bfd267a.
ECHA (European Chemicals Agency). (2020t). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Skin irritation/corrosion: 002 Key | Experimental
result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/18080/7/4/2./?documentUUID=e9664689-9fd6-4faf-84ee-d4f68afc622e.
ECHA (European Chemicals Agency). (2020u). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Skin irritation/corrosion: 003 Supporting |
Experimental result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/18080/7/4/2/?documentUUID=c7892408-706c-426a-8c50-f66339fe2fb0.
ECHA (European Chemicals Agency). (2020v). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Skin sensitisation: 001 Key | Experimental result.
https://echa.europa.eu/registration-dossier/-/registered-
dossier/18080/7/5/2/?documentU UID=9b656fd5-4459-4ff3-8403-d 18b311f7847.
ECHA (European Chemicals Agency). (2020w). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Skin sensitisation: 002 Key | Experimental result.
https://echa.europa.eu/registration-dossier/-/registered-
dossier/18080/7/5/2/?documentUUID=c3c6148f-e63a-4f80-9c2a-6239c9f16856.
ECHA (European Chemicals Agency). (2020x). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Skin sensitisation: 003 Supporting |
Experimental result. https://echa.europa.eu/registration-dossier/-/registered-
dossier/18080/7/5/2/?documentUUID=lb43f008-0633-478b-9a43-ee7cl2ffl4ac.
ECHA (European Chemicals Agency). (2020y). Registration Dossier: Lithium
bis(trifluoromethylsulfonyl)imide (90076-65-6): Toxicity to reproduction: Key | Experimental
Result. https://echa.europa.eu/registration-dossier/-/registered-dossier/18080/7/9/2.
Evidence Partners. (2022). DistillerSR. Retrieved from
https://www.evidencepartners.com/products/distillersr-systematic-review-software/
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polyfluoroalkyl substance toxicity and human health review: Current state of knowledge and
strategies for informing future research [Review], Environ Toxicol Chem 40: 606-630.
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Fox, JR; Hogan, KA; Davis, A. (2016). Dose-response modeling with summary data from developmental
toxicity studies. Risk Anal 37: 905-917. http://dx.doi.org/10.llll/risa.12667.
Hall, AP; Elcombe, CR; Foster, JR: Harada, T; Kaufmann, W; Knippel, A; Kuttler, K; Malarkey, DE;
Maronpot, RR: Nishikawa, A: Nolte, T: Schulte, A: Strauss, V: York, Ml (2012). Liver hypertrophy:
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International ESTP Expert Workshop [Review], Toxicol Pathol 40: 971-994.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Hekster, FM; Laane, RWP, M; de Voogt, P. (2003). Environmental and toxicity effects of
perfluoroalkylated substances [Review], In GW Ware (Ed.), Reviews of environmental
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for systematic review. Syst Rev 5: 87. http://dx.doi.org/10.1186/sl3643-016-Q263-z.
Huntingdon Research Center. (1992a). T-4201: Bacterial mutation assay. (3M-EPA-00308051; MIN
82/921076). St. Paul, MN: 3M Toxicology Services.
Huntingdon Research Center. (1992b). T-4201: Seven-day preliminary oral toxicity study in rats. (3M-
EPA-00308332; 920962D/MIN 79/ST). St. Paul, MN: 3M Toxicology Services.
Huntingdon Research Center. (1993a). T-4201: 4-week oral toxicity study in rats with 2-week recovery
period. (3M-EPA-00202912; MIN 80/921461). St. Paul, MN: 3M Toxicology Services.
Huntingdon Research Center. (1993b). T-4201: Analysis of metaphase chromosomes obtained from CHL
cells cultured in vitro. (3M-EPA-00309109; MIN 84/930238). St. Paul, MN: 3M Toxicology
Services.
Huntingdon Research Center. (1993c). T-4201: Metaphase chromosome analysis of human lymphocytes
cultured in vitro. (3M-EPA-00307701; MIN 83/930237). St. Paul, MN: 3M Toxicology Services.
Huntingdon Research Center. (1993d). T-4201: Physico-chemical properties. (3M-EPA-00308451; MIN
78/921393). St. Paul, MN: 3M Toxicology Services.
Maronpot, RR. (2014). Liver - Extramedullar hematopoiesis. In National Toxicology Program
nonneoplastic lesion atlas. Research Triangle Park, NC: National Toxicology Program.
https://ntp.niehs.nih.gov/nnl/hepatobiliary/liver/emh/index.htm.
NASEM (National Academies of Sciences, Engineering, and Medicine). (2018). Progress toward
transforming the Integrated Risk Information System (IRIS) program: A 2018 evaluation.
Washington, DC: National Academies Press, http://dx.doi.org/10.17226/25086.
NASEM (National Academies of Sciences, Engineering, and Medicine). (2021). Review of U.S. EPA's ORD
staff handbook for developing IRIS assessments: 2020 version. Washington, DC: National
Academies Press, http://dx.doi.org/10.17226/26289.
Radke, EG: Braun, JM: Meeker, JD: Cooper, GS. (2018). Phthalate exposure and male reproductive
outcomes: A systematic review of the human epidemiological evidence [Review], Environ Int
121: 764-793. http://dx.doi.Org/10.1016/i.envint.2018.07.029.
Sciome (Sciome, LLC.). (2023). SWIFT-Active Screener. Retrieved from https://www.sciome.com/swift-
activescreener/
Sunderland, EM: Hu, XC; Dassuncao, C; Tokranov, AK; Wagner, CC; Allen, JG. (2019). A review of the
pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present
understanding of health effects [Review], J Expo Sci Environ Epidemiol 29: 131-147.
http://dx.doi.org/10.1038/s41370-018-0Q94-l.
U.S. EPA (U.S. Environmental Protection Agency). (1988). Recommendations for and documentation of
biological values for use in risk assessment [EPA Report], (EPA600687008). Cincinnati, OH.
http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=34855.
U.S. EPA (U.S. Environmental Protection Agency). (1991). Guidelines for developmental toxicity risk
assessment. Fed Reg 56: 63798-63826.
U.S. EPA (U.S. Environmental Protection Agency). (1994). Methods for derivation of inhalation reference
concentrations and application of inhalation dosimetry [EPA Report], (EPA600890066F).
Research Triangle Park, NC.
https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=71993&CFID=51174829&CFTOKEN=250
06317.
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
U.S. EPA (U.S. Environmental Protection Agency). (2002). A review of the reference dose and reference
concentration processes. (EPA630P02002F). Washington, DC.
https://www.epa.gov/sites/production/files/2014~12/documents/rfd~final.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk assessment [EPA
Report], (EPA630P03001F). Washington, DC. https://www.epa.gov/sites/production/files/2013~
09/documents/cancer guidelines final 3~25~05.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2011). Recommended use of body weight 3/4 as the
default method in derivation of the oral reference dose. (EPA100R110001). Washington, DC.
https://www.epa.gov/sites/production/files/2013~09/documents/recommended~use~of~
bw34.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2012). Benchmark dose technical guidance [EPA
Report], (EPA100R12001). Washington, DC: U.S. Environmental Protection Agency, Risk
Assessment Forum, https://www.epa.gov/risk/benchmark~dose~technical~guidance.
U.S. EPA (U.S. Environmental Protection Agency). (2018). Chemistry Dashboard. Washington, DC.
Retrieved from https://comptox.epa.gov/dashboard
U.S. EPA (U.S. Environmental Protection Agency). (2020). PFAS 150 (2020) downloads.
https://hawc.epa.gov/assessment/100500Q85/downloads/.
U.S. EPA (U.S. Environmental Protection Agency). (2021a). CompTox Chemicals Dashboard:
Perfluoropropanoic acid 422-64-0 | DTXSID8059970.
https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID8059970.
U.S. EPA (U.S. Environmental Protection Agency). (2021b). Health Assessment Workspace Collaborative
(HAWC). https://hawc.epa.gov/portal/.
U.S. EPA (U.S. Environmental Protection Agency). (2021c). Human health toxicity values for
hexafluoropropylene oxide (HFPO) dimer acid and its ammonium salt (CASRN 13252-13-6 and
CASRN 62037-80-3). Also known as "GenX chemicals." Final report [EPA Report], (EPA-822R-21-
010). Washington, DC: U.S. Environmental Protection Agency, Office of Water.
U.S. EPA (U.S. Environmental Protection Agency). (2021d). Human health toxicity values for
perfluorobutane sulfonic acid (CASRN 375-73-5) and related compound potassium
perfluorobutane sulfonate (CASRN 29420-49-3) [EPA Report], (EPA/600/R-20/345F).
Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development.
https://cfpub.epa.gov/ncea/risk/recordisplav.cfm?deid=350888.
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acid (PFBA) and related compound ammonium perfluorobutanoic acid (public comment and
external review draft, Aug 2021) [EPA Report], (EPA/635/R-20/424a). Washington, DC: U.S.
Environmental Protection Agency, Integrated Risk Information System.
https://nepis.epa.gov/Exe/ZyPURL. cgi?Dockey=P1014IBF.txt.
U.S. EPA (U.S. Environmental Protection Agency). (2022). ORD staff handbook for developing IRIS
assessments [EPA Report], (EPA 600/R-22/268). Washington, DC: U.S. Environmental Protection
Agency, Office of Research and Development, Center for Public Health and Environmental
Assessment, https://cfpub.epa.gov/ncea/iris drafts/recordisplay.cfm?deid=356370.
U.S. EPA (U.S. Environmental Protection Agency). (2023). CompTox Chemicals Dashboard: Lithium
bis[(trifluoromethyl)sulfonyl]azanide 90076-65-6 | DTXSID8044468.
https://comptox.epa.gov/dashboard/chemical/details/DTXSID8044468.
Whalan, JE. (2015). A toxicologist's guide to clinical pathology in animals: Hematology, clinical chemistry,
urinalysis. Switzerland: Springer International Publishing, http://dx.doi.org/10.1007/978~3~319~
15853-2.
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Yamamoto, K; Miwa, Y: Abe-Suzuki, S; Abe, S; Kirimura, S; Onishi, I: Kitagawa, M; Kurata, M. (2016).
Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche
(Review) [Review], Mol Med Rep 13: 587-591. http://dx.doi.org/10.3892/mmr.2015.4621.
Yost, EE: Euling, SY; Weaver, JA; Beverly, BEJ; Keshava, N: Mudipalli, A; Arzuaga, X: Blessinger, T; Dishaw,
L: Hotchkiss, A: Makris, SL. (2019). Hazards of diisobutyl phthalate (DIBP) exposure: A systematic
review of animal toxicology studies [Review], Environ Int 125: 579-594.
http://dx.doi.Org/10.1016/i.envint.2018.09.038.
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APPENDIX A.ASYSTEMATIC LITERATURE SEARCH METHODS AND RESULTS
Methods
The following describes the systematic review methods used to collect available
epidemiologic and toxicological data for Lithium bis[(trifluoromethyl)sulfonyl]azanide
(HQ-115) and l,l,l-Trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (TFSI). The
methods used here are consistent with the ORD Staff Handbook for Developing Integrated Risk
Information System Assessments (Version 2.0, referred to as the draft "IRIS Handbook") Qj.S.
EPA. 20221
Populations, Exposures, Comparators, and Outcomes (PECO) Criteria and Supplemental
Material Tagging
PECO criteria are used to focus the scope of an evidence map or systematic review by
defining the research question(s), search terms, and inclusion/exclusion criteria. The PECO
criteria for HQ-115 is presented in Table A-l. In addition to PECO-relevant studies, studies that
did not meet PECO criteria but contained "potentially relevant" supplemental material were
tracked during the literature screening process. Supplemental material was tagged by category, as
outlined in Table A-2. Note that "supplemental" material does not refer to findings contained in
the supplement of papers identified.
Literature Search and Screening Strategies
Database Search Term Development
The databases listed below were searched for literature containing the chemical search
terms. Full details of the search strategy (including the search strings) for each database are
presented in detail in EPA's Health and Environmental Research Online (HERO) database
(https://heronet.epa.eov/heronet/index.cfm/proiect/paee/proiect id/3044). The HERO database
(https://hero.epa.eov/) is used to provide access to the scientific literature used in EPA's science
assessments, including this effort.
• PubMed (National Library of Medicine)
• Web of Science (WOS, Thomson Reuters)
The literature search for HQ-115 and TFSI focused on the chemical name (and synonyms
or trade names) with no additional limits. Chemical synonyms were identified by using
synonyms in the Dashboard ( £02 la). The preferred chemical name (as presented in
the Dashboard), Chemical Abstract Services Registry Number (CASRN), and synonyms were
then shared with EPA information specialists who used these inputs to develop search strategies
tailored for PubMed, and WOS.
Database Searches
The database searches were conducted by an EPA information specialist in August 2021
and updated in November 2022. All records were stored in EPA's HERO database. References
were deduplicated in HERO by an EPA information specialist using unique identifiers (e.g.,
PMID, WOSID, or DOI) and reference information (Title, Author, Year, Journal, etc). Following
deduplication, SWIFT-Review software (Sciome. 2023; Howard et at.. 2016) was used to
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identify which of the unique references were most relevant for human health risk assessment. In
brief, SWIFT-Review was used to+ filter the unique references based on the software's preset
literature search strategies (titled "evidence stream"). These evidence streams were developed by
information specialists and can be used to separate the references most relevant to human health
from those that are not (e.g., environmental fate studies). References are tagged to a specific
evidence stream if the search terms from that evidence stream appear in the title, abstract,
keyword, and/or medical subject headings (MeSH) fields of that reference. For this assessment,
the following SWIFT-Review evidence stream filters were applied: human, animal models for
human health, and in vitro studies. Specific details on the evidence stream search strategies are
available through Sciome's SWIFT-Review documentation at https://www.sciome.com/wp-
content/uploads/2019/08/SWIFT-Review-Search-Strategies-Evidence-Stream.docx. Studies not
retrieved using the search strategies were not considered further
Other Resources Consulted
The literature search strategies described above are designed to be broad, but like any
search strategy, studies may be missed (e.g., cases where the specific chemical is not mentioned
in title, abstract, or keyword content; "grey" literature that is not indexed in the databases listed
above). Additionally, if incomplete citation information was provided (e.g., if reference lists
searched did not include titles) no additional searching was conducted. Thus, in addition to the
databases identified above, the sources below were used to identify studies that may have been
missed during the database search:
• The Endocrine Disruptor Exchange (TEDX).https://pfastoxdatabase.ore/
• National Toxicology Program (NTP) database of Chemical Effects in Biological
Systems (CEBS). https://cebs.niehs.nih.eov/cebs/
• References from EPA's CompTox Chemicals Dashboard ToxValDB (Toxicity
Values Database) (U.S. EPA. 2018) to identify studies or assessments that present
point of departure (POD) information. ToxValDB collates publicly available
toxicity dose-effect related summary values typically used in risk assessments.
Many of the PODs presented in ToxValDB are based on grey literature studies or
assessments not available in databases such as PubMed, Web of Science (WoS),
etc. It is important to note that ToxValDB entries have not undergone quality
control to ensure accuracy or completeness and may not include recent studies.
o ToxValDB includes POD data collected from data sources within ACToR
(Aggregated Computational Toxicology Resource) and ToxRefDB
(Toxicity Reference Database) and no-observed and lowest-observed
(adverse) effect level (NOEL, NOAEL, LOEL, LOAEL) data extracted
from repeated dose toxicity studies submitted under REACH
(Registration, Evaluation, Authorisation and Restriction of Chemicals).
Also included are reference dose and concentration values (RfDs and
RfCs) from EPA's Integrated Risk Information System (IRIS) and dose
descriptors from EPA's Provisional Peer-Reviewed Toxicity Values
(PPRTV) documents. Acute toxicity information in ToxValDB comes
from several sources, including Organization for Economic Cooperation
and Development (OECD) eChemPortal, National Library of Medicine
(NLM), Hazardous Substances Data Bank (HDSB), ChemlDplus via EPA
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Toxicity Estimation Software Tool (TEST), and the European Union (EU)
Joint Research Centre (JRC) AcutoxBase and the EU COSMOS project
and the European Chemicals Agency (ECHA) registration dossiers to
identify data submitted by registrants, available at
http://echa.europa.eu/information-on-chemicals/information-from-
existing-substances-regulation. (ECHA, 2020)
• European Chemicals Agency (ECHA) registration dossiers to identify data
submitted by registrants, available at http://echa.europa.eu/information-on-
chemicals/information-from-existing-substances-regulation. (ECHA. 2020a).
Each grey literature source was searched using specific identifiers required by the source
(CASRN or DSSTox substance identifier (DTXSID)). If no results were retrieved using these
identifiers, HQ-115 was searched on the chemical name if allowed by the source, no additional
limits were used. Chemical identifiers for the chemical were identified through searching by
chemical name, CASRN or DTXSID in the Dashboard ( 21a).
Screening and Tagging Process
The studies identified from the database searches were imported into DistillerSR
(Evidence Partners. 2022) for title or abstract (T1AB) and full text screening. DistillerSR is a
web-based collaborative software application to track literature and screening responses from
two independent reviewers; each reviewer screens each title and abstract or full text to identify
references as meeting PECO criteria, containing potentially supplemental content and what type
of supplemental content, as well as references that do not meet PECO criteria or do not contain
supplemental information. Supplemental content tags are described in Table A-2. References
were first screened for PECO criteria at the DistillerSR TIAB level, then any references
potentially meeting PECO again by reviewing the full text of the reference. If PECO relevance
was unclear at the TIAB level, screeners erred on inclusion and moved those references forward
to full text screening. Conflicts between the independent reviewers were resolved by discussion.
Declassified CBI studies obtained were title or abstract (TIAB) and full text screened for
meeting PECO criteria, containing potentially supplemental content and what type of
supplemental content, as well as references that do not meet PECO criteria or do not contain
supplemental information.
No human epidemiological studies were identified as PECO relevant or supplemental.
Animal studies that met PECO criteria after full-text review and were repeat dose studies of 21-
day and longer durations, or with study designs focusing on exposure windows targeting
reproduction or development, were prioritized for evaluation and extraction. Studies meeting
these exposure timing and duration parameters were moved forward for study evaluation
(described in next section) and endpoint level data extraction. All other animal studies identified
as PECO relevant or supplemental were not evaluated or extracted, but methods and results (if
reported) were summarized in this assessment document.
Data Extraction of Study Methods and Findings
Data extraction was conducted for prioritized animal toxicology studies by two members
of the evaluation team using EPA's version of Health Assessment Workspace Collaborative
(HAWC) (I. c. < ^ \ 4V) h)> a free ar|d open source web-based software application designed to
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manage and facilitate the process of conducting literature assessments. Data extracted included
basic study information (e.g., full citation, funding, author-reported conflicts of interest);
experiment details (e.g., study type, chemical name, chemical source, and purity); animal group
specifics (species, strain, sex, age at exposure and assessment, husbandry); dosing regimen;
endpoints evaluated; and results (qualitative or quantitative) by endpoint. No attempts were made
to contact authors for information that was not reported in a study. Data extraction was
performed by one member of the evaluation team (primary extractor) and checked by a second
member for completeness and accuracy (secondary extractor). Data extraction results were used
to create HAWC visualizations to highlight observed effects that informed the assessment. The
detailed HAWC extraction for animal studies are available for download from EPA HAWC in
Excel format at https://hawc.epa.gov/assessment/public/ ( ,020).
Subsequent to HAWC data extraction, a toxicologist reviewed each study to identify
study level no observed adverse effect levels [NOAELs] and lowest observed adverse effect
levels [LOAELs], These judgements were made at the individual study level.
Study Evaluation
Study evaluation was conducted for prioritized animal toxicology studies (>21 day
exposure durations or exposure occurring during reproduction or development) by two reviewers
using EPA's version of HAWC ( £02 lb). Reviews were made by toxicologists with
multiple years of experience in developing chemical human health assessments. During study
evaluation, in each evaluation domain, at least two reviewers reached a consensus rating of
Good, Adequate, Deficient, Not Reported or Critically Deficient as defined in HAWC. Key
concerns were potential sources of bias (factors that could systematically affect the magnitude or
direction of an effect in either direction) or insensitivity (factors that limit the ability of a study to
detect a true effect). Core and prompting questions used to guide the judgment for each domain
are described in more detail in the IRIS Handbook ( 12). No attempts were made to
contact authors for information that was not reported in a study. Once the evaluation domains
were rated, the identified strengths and limitations were considered to reach an overall study
confidence rating of High, Medium, Low, or Uninformative for a specific health outcome. The
ratings, which reflect a consensus judgment between reviewers, are defined as follows:
• High: A well-conducted study with no notable deficiencies or concerns identified
for the outcome(s) of interest; the potential for bias is unlikely or minimal, and the
study used sensitive methodology. "High" confidence studies generally reflect
judgments of good across all or most evaluation domains.
• Medium: A study where some deficiencies or concerns were noted for the
outcome(s) of interest, but the limitations are unlikely to be of a notable degree.
Generally, "medium" confidence studies will include adequate or good judgments
across most domains, with the impact of any identified limitation not being
judged as severe.
• Low: A study where one or more deficiencies or concerns were noted for the
outcome(s) of interest, and the potential for bias or inadequate sensitivity could
have a significant impact on the study results or their interpretation. Typically,
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"low" confidence studies would have a deficient evaluation for one or more
domains, although some "medium" confidence studies may have a deficient rating
in domain(s) considered to have less influence on the magnitude or direction of
the results. Generally, in an assessment context (or a full systematic review), low
confidence results are given less weight compared to high or medium confidence
results during evidence synthesis and integration and are generally not used as the
primary sources of information for hazard identification or derivation of toxicity
values unless they are the only studies available. Studies rated as "low"
confidence only because of sensitivity concerns about biases towards the null
would require additional consideration during evidence synthesis.
• Uninformative: A study where serious flaw(s) make the results unusable for
informing hazard identification for the outcome(s) of interest. Studies with
critically deficient j udgments in any evaluation domain will almost always be
classified as "uninformative" (see explanation above). Studies with multiple
deficient judgments across domains may also be considered "uninformative." As
mentioned above, although outside the scope of this assessment, in an assessment
or full systematic review uninformative studies would not be considered during
the synthesis and integration of evidence for hazard identification or for dose
response but might be used to highlight possible research gaps. Thus, data from
studies deemed uninformative are not depicted in the results displays included in
this assessment.
Rationales for each study evaluation classification, including a brief description of any
identified strengths and/or limitations from the domains and their potential impact on the overall
confidence determination, are documented and retrievable in HAWC, https://hawc.epa.eov/.
51
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table A-l. PECO Criteria
PIX O element
Description
Populations
Human: Any population and life stage (occupational or general population, including children
and other potentially sensitive populations).
Animal: Nonhuman mammalian animal species (whole organism) of any lifestage (including
preconception, in utero, lactation, peripubertal, and adult stages).
Exposures
Two relevant forms:
1. HQ-115, LiTFSI, lithium bis[(trifluoromethyl)sulfonyl]azanide,
Methanesulfonamide, l,l,l-trifluoro-N-[(trifluoromethyl)sulfonyl]-, lithium salt
(1:1). Fluorad HO 115. or anv other svnonvms found on the ComoTox
Dashboard Daee.
2. l,l,l-Trifhioro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide, HNTf2, or any
other svnonvms found on the ComoTox Dashboard Daee.
Human: Any exposure to via the oral and inhalation routes. Studies will also be included
if biomarkers of HQ-115 exposure are evaluated (e.g., measured HQ-115 in tissues or bodily
fluids) but the exposure route is unclear or reflects multiple routes. Other exposure routes,
including dermal will be tracked during title and abstract screening and tagged as potentially
relevant supplemental information.
Animal: Any exposure via the oral and inhalation routes. Studies involving exposures to
mixtures will be included only if they include an arm with exposure to a HQ-115 alone. Other
exposure routes, including dermal or injection, will be tracked during title and abstract
screening and tagged as potentially relevant supplemental information.
Comparators
Human: A comparison or referent population exposed to lower levels (or no exposure/
exposure below detection limits) of HQ-115, or exposure to HQ-115 for shorter periods of
time. However, worker surveillance studies are considered to meet PECO criteria even if no
referent group is presented. Case reports describing findings in 1-3 people in non-occupational
or occupational settings will be tracked as potentially relevant supplemental information.
Animal: A concurrent control group exposed to vehicle only treatment and/or untreated
control (control could be a baseline measurement). Acute toxicity studies without a control
group are considered to meet PECO criteria if the outcome is mortality and the baseline of
alive can be used as the comparator.
Outcomes
All health outcomes (cancer and noncancer).
52
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Table A-2. Major categories of potentially relevant supplemental material
C'alegorv
Description
In vitro, ex vivo, or in
silico "mechanistic"
studies
In vitro, ex vivo, or in silico studies reporting measurements related to a health
outcome that inform the biological or chemical events associated with phenotypic
effects, in both mammalian and non-mammalian model systems.
Absorption, Distribution,
Metabolism, and Excretion
(ADME)
AD ME studies are primarily controlled experiments where defined exposures
usually occur by intravenous, oral, inhalation, or dermal routes, and the
concentration of particles, a chemical, or its metabolites in blood or serum, other
body tissues, or excreta are then measured. These data are used to estimate the
amount absorbed (A), distributed to different organs (D), metabolized (M), and/or
excreted/eliminated (E) through urine, breathe, feces, etc.
• ADME data can also be collected from human subjects who have had
environmental or workplace exposures that are not quantified or fully defined.
However, to be useful such data must involve either repeated measurements
over a time-period when exposure is known (e.g., is zero because previous
exposure ended) *or* time- and subject-matched tissue or excreta
concentrations (e.g., plasma and urine, or maternal and cord blood).
• ADME data, especially metabolism and tissue partition coefficient
information, can be generated using in vitro model systems. Although in vitro
data may not be as definitive as in vivo data, these studies should also be
tracked as ADME. For large evidence bases it may be appropriate to separately
track the in vitro ADME studies.
* Studies describing environmental fate and transport or metabolism in bacteria are
not tagged as ADME.
Classical Pharmacokinetic
(PK) Model Studies, or
Physiologically based
Pharmacokinetic (PBPK)
Model studies
Classical PK or Dosimetry Model Studies: Classical PK or dosimetry modeling
usually divides the body into just one or two compartments, which are not specified
by physiology, where movement of a chemical into, between, and out of the
compartments is quantified empirically by fitting model parameters to ADME data.
PBPK or Mechanistic Dosimetry Model Studies: PBPK models represent the bodv
as various compartments (e.g., liver, lung, slowly perfused tissue, richly perfused
tissue) in order to quantify the movement of chemicals or particles into and out of
the body (compartments) by defined routes of exposure, metabolism and
elimination, and thereby estimate concentrations in blood or target tissues.
Non-mammalian model
systems
Studies in non-mammalian model systems, e.g,,Xenopus, fish, birds, C. elegans.
Transgenic mammalian
model systems
Transgenic studies in mammalian model systems.
Non-oral or non-inhalation
routes of administration
Studies in which humans or animals (whole organism) were exposed via a non-oral
or non-inhalation route (e.g., injection, dermal exposure).
Exposure characteristics
(no health outcome
assessment)
Exposure characteristic studies include data that are unrelated to health outcomes,
but which provide information on exposure sources or measurement properties of
the environmental agent (e.g., demonstrate a biomarker of exposure).
Mixture studies
Mixture studies that are not considered PECO-relevant because they do not contain
an exposure or treatment group assessing only the chemical of interest. This
category is generally used for experimental studies and generally does not apply to
epidemiological studies where the exposure source may be unclear.
53
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Csilefiorv
Description
( ase reports
Case reports describing health outcomes alter exposure will be tracked as
potentially relevant supplemental information when the number of subjects is < 3.
Records with no original
data
Records that do not contain original data, such as other agency assessments,
informative scientific literature reviews, editorials, or commentaries.
Conference abstracts
Records that do not contain sufficient documentation to support study evaluation
and data extraction.
Republished PECO
relevant data
PECO relevant publications that report on the same study as another PECO relevant
reference. For example, ECHA dossiers and industry correspondence letters that
report data from the same single study.
54
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
APPENDIX B.BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR CONTINUOUS NONCANCER DATA
Benchmark dose (BMD) modeling of continuous data is conducted with U.S. EPA's
BMDS (Version 3.2). All continuous models available within the software are fit using a BMR
of 1 standard deviation (SD) relative risk or 10% extra risk when a biologically determined BMR
is available (e.g., BMR 10% relative deviation [RD] for body weight based on a biologically
significant weight loss of 10%), as outlined in the Benchmark Dose Technical Guidance (U.S.
EPA. 2012). A BMR 10% RD for relative liver weights is considered a minimally biologically
significant response in adult animals and was applied in this assessment for BMD modeling
purposes. The default BMR of 1 SD was also applied for comparison. An adequate fit is judged
based on the %2 goodness-of-fit p-value (p > 0.1), magnitude of the scaled residuals near the
BMR, and visual inspection of the model fit. In addition to these three criteria forjudging
adequacy of model fit, a determination is made as to whether the variance across dose groups is
homogeneous. If a homogeneous variance model is deemed appropriate based on the statistical
test provided by BMDS (i.e., Test 2), the final BMD results are estimated from a homogeneous
variance model. If the test for homogeneity of variance is rejected (p < 0.1), the model is run
again while modeling the variance as a power function of the mean to account for this
nonhomogeneous variance. If this nonhomogeneous variance model does not adequately fit the
data (i.e., Test 3; P<0. 1), the data set is considered unsuitable for BMD modeling. Among all
models providing adequate fit, the lowest BMDL/benchmark concentration lower confidence
limit (BMCL) is selected if the BMDL/BMCL estimates from different models vary >threefold;
otherwise, the BMDL/BMCL from the model with the lowest AIC is selected as a potential POD
from which to derive the oral reference dose or inhalation reference concentration (RfD/RfC).
55
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Model Predictions for Increased Relative Liver Weight in Male Rats (Huntingdon
Research Center. 1993a)
The procedure outlined above for continuous data was applied to the data for increased
relative liver weight in adult male Sprague-Dawley rats exposed to HQ-115 for 28-days via
gavage (Huntingdon Research Center, 1993a). The BMD modeling results are summarized in
Table B-l and Figure B-l. The constant variance model provided adequate fit to the variance
data, and adequate fit to the means was provided by some included models. The BMDLs for the
models providing adequate fit are sufficiently close (i.e., differ by
-------
Human Health Toxicity Values for lithium bis[(trifhioromethyl)sulfonyl]azanide (HQ-1J5)
Frequentist Exponential Degree 2 Model with BMR of 0.1 Rel. Dev. for the BMD and 0.95
Lower Confidence Limit for the BMDL
10
7
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Model Predictions for Increased Relative Liver Weight in Female Rats (Huntingdon
Research Center. 1993a)
The procedure outlined above for continuous data was applied to the data for increased
relative liver weight in adult female Sprague-Dawley rats exposed to HQ-115 for 28-days via
gavage (Huntingdon Research Center, 1993a). The BMD modeling results are summarized in
Table B-2 and Figure B-2. The constant variance model provided adequate fit to the variance
data, and adequate fit to the means was provided by some included models. The BMDLs for the
models providing adequate fit are sufficiently close (i.e., differ by
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Human Health Toxicity Values for lithium bis[(trifhioromethyl)sulfonyl]azanide (HQ-1J5)
Frequentist Exponential Degree 2 Model with BMR of 0.1 Rel. Dev. for the BMD and
0.95 Lower Confidence Limit for the BMDL
9
s
Estimated Probability
Response at BMD
C Data
BMD
BMDL
60
Figure B-2. Fit of Exponential 2 Model to Data for Increased Relative Liver Weight
in Adult Female Sprague Dawley Rats Exposed to HQ-115 for 28-days via Gavage
(Huntingdon Research Center, 1993a).
BMD Model Output for Figure B-2:
Model Results
Benchmark Dose
BMD
15.58828354
BMDL
12.8318022
BMDU
19.9271384
AIC
39.23315775
T est 4 P-value
0.580854184
D.O.F.
2
Model Parameters
# of Parameters
3
Variable
Estimate
a
5.076904278
b
0.006114221
log-alpha
-1.176219177
Goodness of Fit
Dose
Size
Estimated
Calc'd
Observed
Estimated
Calc'd SD
Observed
Scaled
Median
Median
Mean
SD
SD
Residual
0
5
5.076904278
4.93
4.93
0.55537618
0.248
0.248
-0.591469281
1.67
5
5.129008837
5.33
5.33
0.55537618
0.721
0.721
0.809235106
10
5
5.397003515
5.34
5.34
0.55537618
0.519
0.519
-0.229508825
60
5
7.326917982
7.33
7.33
0.55537618
0.781
0.781
0.012408888
Likelihoods of Interest
Model
Log Likelihood*
# of Parameters
AIC
A1
-16.07332335
5
42.1466467
A2
-13.02496418
8
42.0499284
A3
-16.07332335
5
42.1466467
fitted
-16.61657888
3
39.2331578
R
-29.95010849
2
63.900217
* Includes additive constant of-18.37877. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
Test
-2*Log(Likelihood
Ratio)
Test df
p-value
1
33.85028862
6
<0.0001
2
6.096718329
3
0.10699832
3
6.096718329
3
0.10699832
4
1.086511056
2
0.58085418
59
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Model Predictions for Increased Serum Alkaline Phosphatase (ALP) in Male Rats
(Huntingdon Research ("enter. 1993a)
The procedure outlined above for continuous data was applied to the data for increased
serum ALP in adult male Sprague-Dawley rats exposed to HQ-115 for 28-days via gavage
(Huntingdon Research Center, 1993a). The BMD modeling results are summarized in Table B-3
and Figure B.3. The constant variance model provided adequate fit to the variance data, and
adequate fit to the means was provided by some included models. The BMDLs for the models
providing adequate fit are sufficiently close (i.e., differ by
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
Frequentist Polynomial Degree 3 Model with BMR of 1 Std. Dev.
for the BMD and 0.95 Lower Confidence Limit for the BMDL
700
600
500
400
' 300
200
100
0
4 TT
Estimated Probability
Response at BMD
O Data
BMD
BMDL
30
Dose
Figure B-3. Fit of Polynomial 3 Model to Data for Increased Serum ALP in Adult
Female Sprague Dawley Rats Exposed to HQ-115 for 28-days via Gavage
(Huntingdon Research Center, 1993a).
BMD Model Output for Figure B-3:
Model Resnlts
Benchmark Dose
BMD
45.4340744
BMDL
20.05903987
BMDU
55.38452434
AIC
224.6293083
Test 4 P-
value
0.71905267S
D.O.F.
2
Model Parameters
#of
Parameters
5
Variable
Estimate
2
366.1548637
betal
Bounded
beta2
Bounded
beta3
0.000610036
alpha
3273.412651
Goodness of Fit
Dose
Size
Estimated
Median
csks
Median
Observed
Mean
Estimated
SD
SD
Observed
SD
Scaled
Residual
0
5
366.1548637
376
376
57.2137453
65.98
65.98
0.384774566
1.67
5
366.1577049
373
373
57.2137453
46.5
46.5
0.267415406
10
5
366.7648992
350
350
57.2137453
66.56
66.56
0.655217624
60
5
497.9225322
498
498
57.2137453
69.93
69.93
0.003027651
Likelihoods of Interest
Model
Log
Likelihood*
# of
Parameters
AIC
A1
108.984S335
5
227.969667
A2
108.5193477
8
233.038695
A3
108.9848335
5
227.969667
fitted
109.3146542
3
224.629308
R
116.2033758
2
236.406752
* Includes additive constant of -18.37877. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
Test
-2*L°g
(Likelihood
Ratio)
Test
p-value
1
15.3680561
6
0.01757934
T
0.930971534
3
0.81794796
3
0.930971534
3
0. SI794796
4
0.659641315
2
0.71905268
61
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
MODELING PROCEDURE FOR DICHOTOMOUS NONCANCER DATA
The BMD modeling of dichotomous data is conducted with the EPA's BMDS (Version
3.2). For these data, the Gamma, Logistic, Log-Logistic, Probit, Log-Probit, Hill, Multistage, and
Weibull dichotomous models available within the software are fit using a BMR of 10% extra risk
for hepatocyte hypertrophy and 1% extra risk for postnatal survival. In general, the BMR should
be near the low end of the observable range of increased risk in the study. BMRs that are too low
can result in widely disparate BMDL estimates from different models (high model dependence).
Adequacy of model fit is judged based on the %2 goodness-of-fit p-value (p > 0.1), magnitude of
scaled residuals (absolute value < 2.0), and visual inspection of the model fit. Among all models
providing adequate fit, the BMDL from the model with the lowest AIC is selected as a potential
POD, if the BMDLs are sufficiently close (less than approximately threefold); if the BMDLs are
not sufficiently close (greater than approximately threefold), model dependence is indicated, and
the model with the lowest reliable BMDL is selected.
Model Predictions for Increased Hepatocyte Hypertrophy in Male Rats (ECHA. 2020r)
The procedure outlined above for dichotomous data was applied to the data for increased
hepatocyte hypertrophy in adult male Sprague-Dawley rats exposed to HQ-115 for 29-days via
gavage (ECHA. 2020f). The BMD modeling results are summarized in Table B-4 and Figures B-
4 and B-5. All models provided adequate fit (p-value >0.10). The BMDLs for the models
providing adequate fit are not sufficiently close (i.e., differ by > threefold), so the model with the
lowest BMDL (Multistage Degree 1) is typically selected. However, the model fit to the
observed data in the lowest dose group is very poor, with the model greatly over-estimating the
response (model response ~ 35% compared to observed response of 0%) (Figure B-4). Further,
the scaled residual for the lowest dose group in the Multistage Degree 1 model (—1.56) is much
larger than other models. Therefore, the results of the Multistage Degree 1 model are discounted
and the model with the lowest AIC is selected, in this case the Probit model (see Figure B-5). For
increased hepatocyte hypertrophy, the BMDLioer of 11 mg/kg-day from this model is selected.
62
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HQ-115)
Table B-4. BMD Modeling Results for Increased Hepatocyte Hypertrophy in Adult
Male Sprague Dawley Rats Exposed to HQ-115 for 29-days via Gavage3
Model
DF
jl Goodness-
of-Fit p-
Valueb
Scaled
Residual at
Dose Nearest
BMD
AIC
BMDioer
(mg/kg-day)
BMDLioer
(mg/kg-day)
Dichotomous
Hill
1
0.9999973
-1.30663E-06
9.004035141
36.82923
10.74789
Gamma
1
0.9999702
-0.047769458
7.008661768
26.92559
9.371798
Log-Logistic
3
0.9999583
-0.000317122
9.004191008
34.80681
10.74744
Multistage 3
3
0.9592595
-0.530058626
7.574609393
18.66666
5.174987
Multistage 2
3
0.8181974
-0.889461309
8.644065015
12.70375
4.166214
Multistage 1
2
0.2016205
-0.00027635
14.21740302
3.912017
2.125352
Weibull
3
0.9996698
-0.106368736
7.026891958
28.54683
8.493537
Logistic
3
0.9999756
2.69659E-05
9.004121944
36.68174
11.57507
Log-Probit
2
0.9999999
-5.67797E-09
9.00402454
33.11154
10.82091
Probit*
3
1
2.12552E-06
7.004025481
34.38414
10.71614
aECHA (2020r)
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
* Selected model. Lowest AIC among models with adequate fit was selected (Probit).
AIC = Akaike's information criterion; ALP = alkaline phosphatase; BMD = maximum likelihood estimate of the
dose associated with the selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR:
i.e., 10ER = dose associated with 10% extra risk from the control); BMR = benchmark response; DF = degree(s) of
freedom.
Frequentist Multistage Degree 1 Model with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Estimated Probability
Response at BMD
— — Linear Extrapolation
O Data
BMD
BMDL
Figure B-4. Fit of Multistage Degree 1 Model to Data for Increased Hepatocyte
Hypertrophy in Adult Male Sprague Dawley Rats Exposed to HQ-115 for 29-days
via Gavage (ECHA, 2020r).
63
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Human Health Toxicity Values for lithium bis[(trifhioromethyl)sulfonyl]azanide (HO-115)
Frequentist Probit Model with BMR of 10% Extra Risk for the
BMD and 0.95 Lower Confidence Limit for the BMDL
©
Estimated Probability
Response at BMD
O Data
BMD
BMDL
90
Figure B-5. Fit of Probit Model to Data for Increased Hepatocyte Hypertrophy in
Adult Male Sprague Dawley Rats Exposed to HQ-115 for 29-davs via Gavage
BMD Model Output for Figure B-5:
Model Results
Benchmark Dose
BMD
34.3841428
BMDL
10.71614352
BMDU
39.2848155
AIC
7.004025481
P-value
1
D.O.F.
3
Chi2
6.22743E-07
Model Parameters
# of Parameters
2
Variable
Estimate
a
-8.158380125
b
Bounded
Goodness ofFit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.69774E-16
8.48869E-16
0
5
-2.914E-08
15
1.24548E-07
6.22739E-07
0
5
-0.0007891
45
0.79999962
3.999998099
4
5
2.126E-06
90
1
5
5
5
0
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test
d.f.
P Value
Full Model
-2.502012118
4
.
-
NA
Fitted Model
-2.50201274
1
1.2455E-06
3
1
Reduced Model
-13.76277627
1
22.5215283
3
<0.0001
0 10 20 30 40 50 60 70 80
Dose
64
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HQ-115)
Model Predictions for Decreased Survival of Offspring at PND4 (ECHA, 2020h,
The procedure outlined above for dichotomous data was applied to the data for decreased
survival of offspring at PND4 in Sprague-Dawley rats exposed to HQ-115 via gavage for 2
weeks before mating, during mating, and until lactational day 4 (ECHA. 2020h); (ECHA.
2020y). The total number of pups (N) in each dose group was estimated from the mean number
of pups/litter and the number of pregnancies (14.1 x 10 = 141 in the control group; 15.2 x 10 =
152 at 15 mg/kg-day; 13.3 x 9 = 120 pups at 30 mg/kg-day) (see Table B-5). The (ECHA.
2020h) (ECHA. 2020y) report did not provide the mean number of fetuses/litter at 60 mg/kg-day,
although mortality was reported at 100% for this group; therefore, the data was modeled without
the highest dose group. The EPA's Benchmark Dose Technical Guidance (U.S. EPA. 2012)
document allows for data to be adjusted by eliminating the high-dose group. Because the focus
of BMD analysis is on the low-dose regions of the response curve, elimination of the high-dose
group is deemed reasonable. Incidences of PND4 survival were estimated from the reported litter
means and viability indices (95.7%, 79.6% and 47.5% for the control, 15 mg/kg-day and 30
mg/kg-day groups, respectively). Viability indices were multiplied times total number of pups
born to calculate the number of pups died on PND4. The data were modeled with standard
BMDS 3.2 dichotomous models after adjusting for litter effects using a Rao-Scott
transformation. Normally, individual animal data are necessary to account for intralitter
correlation present in nested developmental toxicity data (i.e., the observation that pups from one
litter are more likely to respond like one another compared to pups from another litter). But in
this situation, litter level data was not available and instead an approximate approach was used.
Briefly, the numbers of offspring survival were scaled by a design effect in order to approximate
the true variance of the clustered data. This transformation is called the Rao-Scott transformation
and has been shown to reasonably approximate the variance due to clustering and intralitter
correlation in developmental toxicity data (Fox et al.. 2016). Details of the Rao-Scott
transformation are shown in Table B-5. The BMD modeling results are summarized in Table B-6
and Figure B-6.
Given that the offspring survival data only had three dose groups after dropping the high
dose, only models with two parameters (Multistage degree 1, Logistic, and Probit) were used to
model the data. All the models fit to the data provided an adequate fit (p-value <0.1). The
BMDLs for the models providing adequate fit are not sufficiently close (i.e., differ by >
threefold), so the model with the lowest BMDL (Multistage Degree 1) is selected. Therefore, for
decreased PND4 offspring survival, the BMDLier of 0.39 mg/kg-day from this model is
selected.
Table B-5. PND4 Offspring Survival Data Selected for Dose-Response Modeling for
HQ-1153
Doseb
N
Incidence
Percent
Survival
Average Design
Effect0
RS-Nd
RS-
Incidenced
0
141
6
0.04255
2.039078599
69.15
2.94
15
152
31
0.20395
3.531493605
43.04
8.78
30
120
63
0.525
4.921092443
24.38
12.80
Data highlighted in gray was used for dose-response modeling for HQ-115
a ECHA (2020h. 2020v")
65
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Human Health Toxicity Values for lithium bis[(trifluoromethyl)sulfonyl]azanide (HQ-115)
b The high-dose group was eliminated when modeling the offspring survival data because theECHA (2020fa. 2020v)
report did not provide the number of pups/litter in this group to estimate the N and survival incidence.
"'Average design effect is the average of least squares regression and orthogonal regression design effects (Fox et at.
20.1.6').
dThe Rao-Scott transformation (RS) entails dividing the PND4 offspring survival incidence and N by a design effect
to approximate the true variance in the clustered data.
66
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Human Health Toxicity Values for lithium bis[(triflnoromethyl)snlfonyl]azamde (HQ-115)
Table B-6. BMD Modeling Results for Decreased Survival of Offspring at PND4
Exposed to HQ-115 via Gavage3
Model
DF
jl Goodness-
of-Fit /?-Valueb
Scaled
Residual for
Dose Group
near BMD
AIC
BMD
BMDLier
Multistage
Degree 1*
2
0.3065854
0.118017736
107.2412552
0.565085
0.388646
Logistic
2
0.8030267
-0.149037404
105.683223
1.866252
1.26928
Probit
2
0.9943732
-0.003702164
105.6055555
1.632659
1.125964
a(ECHA. 2020h): ECHA (2020v)
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
* Selected model. Lowest BMDL among models with adequate fit was selected (Multistage 1).
AIC = Akaike's information criterion; ALP = alkaline phosphatase; BMD = maximum likelihood estimate of the
dose associated with the selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR:
i.e., 0.01ER = dose associated with 1% extra risk from the control); BMR = benchmark response; DF = degree(s) of
freedom.
Frequentist Multistage Degree 1 Model with BMR of 1% Extra Risk forthe BMD and 0.95
Lower Confidence Limit forthe BMDL
i
0.9
Est mated Probabiity
Response at BMD
Linear Extrapolation
Data
BMD
BMDL
Figure B-6. Fit of Multistage Degree 1 Model to Data for Decreased Survival of
Offspring at PND4s Exposed to HQ-115 via Gavage (ECHA, 2020h), (ECHA,
2020v).
67
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Human Health Toxicity Values for lithium bis[(trifhioromethyl)sulfonyl]azanide (HO-1J5)
BMD Model Output for Figure B-6:
Model Results
Benchmark Dose
BMD
0.565085113
BMDL
0.388646102
BMDU
0.894064467
AIC
107.2412552
P-value
0.306585438
D.O.F.
1
CM2
1.045328481
Slope Factor
0.025730349
Model Parameters
# of Parameters
2
Variable
Estimate
g
0.03968888
bl
0.017785533
Goodness of Pit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.03968888
2.744486032
2.94
69.15
0.11801774
15
0.264556061
11.38649288
8.78
43.04
-0.7724343
30
0.436768173
10.64840806
12.8
24.38
0.65935236
Analysis of Deviance
Model
Log Likelihood
# ofParameters
Deviance
Testd.f.
P Value
Full Model
-50.80274538
3
-
-
NA
Fitted Model
-51.62062761
2
1.635764444
1
0.2009076
Reduced Model
-64.28318787
1
25.32512054
2
<0.0001
68
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