Reactive metabolites can cause drug-induced toxicity and attrition. They are short-lived, electrophilic species formed during Phase I drug metabolism that can covalently bind to macromolecules. While defensive mechanisms usually inactivate them, high doses or individual vulnerabilities can overwhelm these defenses and cause organ or immune toxicity. Common precursors are functional groups like alkyl halides and sulfonates that undergo oxidation to form reactive species like epoxides, imines, and quinones. Understanding reactivity and how to avoid or minimize reactive metabolite formation could improve drug safety.

1. Reactive Metabolites -
Hints How to Avoid a Drug Safety Hazard
Alf Claesson
© 2012-2020 Awametox AB, Stockholm, Sweden. Contact: +4670 553 7131, info@awametox.com. LinkedIn
Reactive
Metabolite
Reactions
with DNA
Reactions
with proteins
Drug
The liver is usually
the first casualty
Problems…problems…problems…problems..problems…problems…

2. 2
Modified from Gerry Kenna and Roger
Bonnert, AstraZeneca
Reactive
Metabolite (RM)
Reactions
with DNA
Reactions
with proteins
• An important cause of drug-induced illness
and fatality, e.g. DILI= Drug Induced Liver Injury
• A major concern for drug industry and regulators
• Low-dose drugs cause less/no problems
Mutagenicity
Carcinogenicity
Teratogenicity
- Benzidine
- Safrole
Target organ toxicity
(reproducible or
idiosyncratic)
- Paracetamol
- Diclofenac
Immune
hypersensitivity
reactions
(idiosyncratic)
- Antibacterial sulfon-
amides
- Halothane
Drug
The liver is usually the
first casualty
N
H2
N
H
S
O
O
N
N OH
Br
Cl
F
F
F

3. 3
Slightly modified from Steve Swallow at the SCI Conference ”Designing Safer Medicines in Discovery:
Current and Emerging Opportunities to Reduce Attrition”, 25th March 2011
Substructural alerts
Genotox/RM
Reactive cpd
Toxic metabolite
(e.g. forms F-acetic
acid)
logP
Light sens.
Solubility
Stability
+ ADME person

4. Substance related failures of drugs are of great concern
Drug safety is a major cause of drug attrition.
 It will take a very long time before we can predict all hazards
 This presentation highlights one factor, i.e. metabolism to reactive
species
– Indeed, we can hope to master this cause of attrition! By
experimentation and increased knowledge
Potency in secondary
test model
Potency in primary test model
Practical
synthesis
Pharmacokinetics
Decreased off-target
I potency
Patent issues
Solubility (for
example)
Lead
CD
Decreased off-
target II potency
Not efficient
22%
Toxicology
32%
Clinical
safety
12%
DMPK
8%
Portfolio
11%
Other reasons
15%

5. 5
The different fates of reactive species formed by
enzymatic actions
In the scheme below “I” represents a drug which acts as an
irreversible inhibitor of a P450 enzyme
– The general term is Mechanism Based Inhibition (MBI) – also
known as suicide inactivation/inhibition.
– Indicated by in vitro experiments where enzymes lose activity by
time, Time Dependent Inhibition (TDI)
P= RM
Covalent binding to
macromolecules
Reaction with water or
glutathion (inactivation)
Extensive MBI of CYPs by a drug is worrysome since it often
leads to interference with metabolism of other drugs (DDI).
There is good correlation between covalent binding of a drug to
proteins and TDI. Nakayama et al. Drug Met Disp 2011, 54, 1247

6.  Reactions that do not occur in most patients at any dose.
 But please don’t call them dose independent; drugs given at a dose of
10 mg/day or less are relatively safe!
 Characteristics suggest immune mechanism
 Also known as hypersensitivity reactions, allergic reactions, type B
reactions, type II reactions
Idiosyncratic Drug Reactions
(Jack Uetrecht’s definition)
6
Some toxicity is reproducible and dose-dependent in animals, e.g.
that of paracetamol (acetaminophen). This is referred to as Type A
toxicity.
For some drugs toxicitiy in man is unpredictable from animal research
and is relatively infrequent. This is referred to as Type B toxicity (truly
idiosyncratic).

7. 7
In real life
Picture to the right from a
presentation by Jack
Uetrecht. Skin injuries are
a common sign of allergic
drug reactions.
Etiologies of acute liver failure in
the US (n = 1,321). Data from the
Acute Liver Failure Study Group
registry, 1998–2008 (W. M. Lee).
Abbreviations: AIH = autoimmune
hepatitis; BCS = Budd–Chiari
syndrome; HAV = hepatitis A virus; HBV
= hepatitis B virus; IDR = idiosyncratic
drug reaction.
acetaminophen

8. Drugs associated with IADRs
Drugs Withdrawn
Aclcofenac (antiinflammatory)
Hepatitis, rash
Alpidem (anxiolytic)
Hepatitis (fatal)
Amodiaquine (antimalarial)
Hepatitis, agranulocytosis
Amineptine (antidepressant)
Hepatitis, cutaneous ADRs
Benoxaprofen (antiinflammatory)
Hepatitis, cutaneous ADRs
Bromfenac (antiinflammatory)
Hepatitis (fatal)
Carbutamide (antidiabetic)
Bone marrow toxicity
Ibufenac (antiinflammatory)
Hepatitis (fatal)
Iproniazid (antidepressant)
Hepatitis (fatal)
Metiamide (antiulcer)
Bone marrow toxicity
Nomifensine (antidepressant)
Hepatitis (fatal), anaemia
Practolol (antiarrhythmic)
Severe cutaneous ADRs
Remoxipride (antipsychotic)
Aplastic anaemia
Sudoxicam (antiinflammatory)
Hepatitis (fatal)
Tienilic Acid (diuretic)
Hepatitis (fatal)
Tolrestat (antidiabetic)
Hepatitis (fatal)
Troglitazone (antidiabetic)
Hepatitis (fatal)
Zomepirac (antiinflammatory)
Hepatitis, cutaneous ADRs
Marketed Drugs
Abacavir (antiretroviral)
Cutaneous ADRs
Acetaminophen (analgesic)
Hepatitis (fatal)
Captopril (antihypertensive)
Cutaneous ADRs, agranulocytosis
Carbamazepine (anticonvulsant)
Hepatitis, agranulocytosis
Clozapine (antipsychotic)
Agranulocytosis
Cyclophosphamide (anticancer)
Agranulocytosis, cutaneous ADRs
Dapsone (antibacterial)
Agranulocytosis, cutaneous ADRs,
aplastic anaemia
Diclofenac (antiinflammatory)
Hepatitis
Felbamate (anticonvulsant)
Hepatitis (fatal), aplastic anaemia
(fatal), severe restriction in use
Furosemide (diurectic)
Agranulocytosis, cutaneous ADRs,
aplastic anaemia
Halothane (anesthetic)
Hepatitis
Imipramine (antidepressant)
Hepatitis
Indomethacin (antiinflammatory)
Hepatitis
Isoniazid (antibacterial)
Hepatitis (can be fatal)
Phenytoin (anticonvulsant)
Agranulocytosis, cutaneous ADRs
Procainamide (antiarrhythmic)
Hepatitis, agranulocytosis
Sulfamethoxazole (antibacterial)
Agranulocytosis, aplastic anaemia
Terbinafine (antifungal)
Hepatitis, cutaneous ADRs
Ticlopidine (antithrombotic)
Agranulocytosis, aplastic anaemia
Tolcapone (antiparkinsons)
Hepatitis (fatal)
Trazodone (antidepressant)
Hepatitis
Trimethoprim (antibacterial)
Agranulocytosis, aplastic anaemia,
cutaneous ADRs
Thalidomide (immunomodulator)
Teratogenicity
Valproic acid (anticonvulsant)
Hepatitis (fatal), teratogenicity
Temp. Withdrawn
or Withdrawn in
other Countries
Aminopyrine (analgesic)
Agranulocytosis
Nefazodone (antidepressant)
Hepatitis (> 200 deaths)
Trovan (antibacterial)
Hepatitis
Zileuton (antiasthma)
Hepatitis
For most of these drugs, bioactivation to reactive metabolites has been demonstrated in vitro or in vivo
Kalgutkar AS and Soglia JR (2005).
Exp. Opin. Drug Metab. & Toxicol. 1:91-141)
Anticancer drugs are conspicuously absent from the lists.

9. 9
Failures of drugs that were on the market or in
clinical trials
Lumiracoxib (Prexige®
from Novartis) launched
2003-2004, withdrawn
autumn 2007 due to
reports of serious liver
adverse events.
Sitaxentan (Encysive
Pharma) was withdrawn in
2010 after having been on
the European market for
only four years.
This compound has obvious
liabilities regarding hazard
for RM formation, yet no
definitive link between ADRs
and RMs.
The mPGES inhibitor LY3031207
was in clinical phase 1 ascending
dose studies (osteoarthritis pain).
Terminated due to the emergence of
liver safety signals, such as
increased alanine aminotransferase.
Mechanism published in 2018.

10. S
O
O O
Alkyl
Alkyl halides and sulfonates
[Br,I,Cl]
Electrophilic esters
SNAr electrophiles
N
A
[F,Cl,Br] N
A
OSO2R
Wide variety of structures! (EWG= electronwithdrawing group)
[F,Cl]
EWG
O
O
Ar
O
O
O N
H
Oxiranes and aziridines
O
SO2
Michael acceptors
Awareness/avoidance of intrinsic reactivity
[F ,C l]
E W G
Very useful presentation at SCI
Conference, March 25, 2011, on
”Designing Safer Medicines in
Discovery”
Title: ChEMBL & Structural Alerts
By Francis Atkinson
Chemogenomics Group
EMBL – EBI, Hinxton
http://www.soci.org/News/Fine-Safer-Medicines-2011-Papers.aspx
10

11. 11
 Shortlived electrophilic intermediates are formed from
many drugs during ‘detoxification’
- Imines and iminium ions from alkylamines
- Epoxides from double bonds
- Unsaturated carbonyls
 Do not cause a safety problem unless
- Defence mechanisms are overwhelmed
- Key macromolecules are altered - manifested by organ
and/or immune toxicity.
 RMs can have selective affinity to certain
macromolecules
- Genotoxicity vs. other organ tox?
- Structure Reactivity/Selectivity Relationships poorly
understood
Reactive metabolites (RMs) from xenobiotics
N
+
O
from paracetamol (acetaminophen); is not extremely
shortlived. Quinoid species very common as RMs.
Most RM-
forming
reactions are
Phase 1
reactions
Most common
RMs listed at
StopRM.org where
references to
reviews are also
found.

12. 12
 Phase 1 reactions, i.e. oxidative (cytochromes P-450),
reductive (-NO2), and hydrolytic pathways. These are
behind most of RM generation.
 Phase 2 reactions, i.e. conjugation reactions like
sulfation and glucuronidation, in general less prone to
cause problems by RM generation.
- Important exceptions are formations of nitrene, quinoid
and carbenium ion species which are initiated by
acetylation, sulfation, and more
- Formation of acylglucuronides and
acyl-CoA thioesters as acylating agents
Metabolic reactions that can generate RMs
All dependent on context - just like organic synthesis…
O
O
O
O
O
H
OH
OH
O
R R= rest of the
drug
R S
O
CoA
Skonberg et al. Exp Op DM Tox 4
(2008) 425
Review

13. The molecular mechanism of genotoxicity by aromatic
amines
Persistent
mutations caused
by intercalated
adducts in hotspots
of DNA lead to
cancer
Repairs
Primary target atom
Nitrenium ion
or nitrene
NH
N
NH
N
N
O
N
H2
H
N
dR
N
NH
N
N
O
N
H2
dR
N
+ H+
P450
+
+ H+
+
NH2
NH
N
NH
N
N
O
N
H2
H
N
dR
N
NH
N
N
O
N
H2
dR
N
Guanine-rich
DNA motif
CYP1A2 Acetyltransferases
H+
+
• Only 30% of arylamines follow this path
• Rate of HO-N formation and nitrenium ion stability
determine mutagenicity.
Sulfotransferases
N
..
N
+
H
N
Reactive nitroso
compounds can also be
formed from anilines
and nitro compounds
DNA products, CRT 2003
See Shamowsky et al. JACS 2011, 133, 16168, and McCarren et al. J
Cheminfo 2011, 3:51

14. 14
Precursors of RMs
 Phenyls/benzene
– Can form arene oxides and quinoid species
– Problem substituents: nitro, amino (anilines and masked
anilines)
– Halo substituents – influence fate of arene oxides
– Alkoxy groups (facilitate hydoxylation and also undergo
dealkylation)
– Alkyl groups on aromatics  HO-alkyl  eliminations to
reactive quinomethanes (benzoquinone methides)
 Heteroaryls
– Thiophenes
– Thiazoles
– Furans, and more…
 Other groups
– Many, e.g. alkenes ( allylic alcohols), alkynes, alkyl
halides. Also carboxylic acids (form acylglucuronides
and thioesters), and more…
Aromatics
Heteroaromatics
Aliphatics
Oxidations by cytochromes P-
450s, FMNs, peroxidases
Reduction

15. 15
Epoxides, especially on aromatic rings (‘arene oxides’)
 Benzene very frequent group in drug candidates
– Lots of varied substituents and fusions
– Indispensible to medicinal chemists?
 RMs formed by epoxidation of the ring
– Labile arene oxides are formed
– As an example, 1,2-naphtalene oxide
was isolated in 1968 by famous NIH
scientists (Daly, Jerina, Witkop et
al. JACS 50 6525)
– Enzymatic inactivation/detoxification
by epoxide hydrolases and/or
GSH S-transferases (also
by direct reaction
with GSH)
GSH is used in vitro to trap some RMs and thus indicate/measure their presence
‘NIH shift’
O
More easily formed than
benzene oxide, E =
70.1 and 59.8 kcal/mol,
respectively (Mats
Svensson, AZ).
Glutathione (GSH)
mM conc. in hepato-
cytes
CYP
O
R
OH
S
G
R
OH
OH
R
OH
R
GSH
H2O
Enzyme
Rearr.

16. 16
Characteristics of dangerous epoxides
 Not inactivated fast enough (in relation to
amounts formed)
 Toxic quantities able to reach and modify
macromolecules
 Learning from experience is possible:
– Polyaromatic oxides are known carcinogens, being
stabilized arene oxides, e.g from benzopyrene
– Other epoxides also have insidious behaviour -
balanced and targeted reactivity towards sensitive
proteins/DNA
O
O
O
‘Stable’ epoxide
from toxic -
naphtoflavone.
Aflatoxins easily form
epoxides on their fused
dihydrofurans (lead to
1,4-dioxo compounds)
O
O
O
O
O O
H
H
N
O
NH2
O
‘Stable’ epoxide from
carbamazepine

17. Lamotrigine is known to form epoxide(s)
NH2
N
N
H2
N
N
Cl
Cl
NH2
N
N
H2
N
N
Cl
Cl
O
Cl
N
N
NH2
N
N
H2
Cl
GS
NH2
N
N
H2
N
N
Cl
Cl
OH
GS
Human
P450 2A6.
Rat P450
2C11
GSH - H2O
M-I M-II
Maggs et al. (2000) and Chen et al. (2009). Both research groups conclude that
a reactive, but somewhat stabilized, epoxide is formed. Formed in minor
amounts in vivo (reaction products isolated from bile only). Notably, it is also
formed in keratinocytes.
The isomeric analogue irsogladine, a PDE4 inhibitor, is metabolized to an
epoxide via a major pathway. This isomerizes to phenols (Sugiyama et al.
Arzneimittelforschung 1986, 36, 1229)
N
N N
Cl
Cl
N
H2 NH2
N
N N
Cl
Cl
N
H2
NH2
O
N
N N
Cl
Cl
N
H2 NH2
OH

18. Quinoids comprise a major category of RMs
O
[C,N,O]
R
OH
[C,N,O]
R
OH
[C,N,O]
Nu
R
Nu
P450 or
other
enzyme
In this large group the electrophilic system consists of a quinone, a quinone-
imine, a quinone-diimine, or the corresponding methides, the quinone
methides (quinomethanes) and quinone-imine methides. Only the para isomers
are depicted below.
Testa et al. (Drug Disc Today 2012, 17, 549) have analysed the literature and
conclude: “A markedly greater source of worry and potential toxicity is seen
with redox reactions, most significantly with the formation of quinones,
quinonimines, quinonimides and quinone-diimines, which accounted for 40%
of all toxic and/or reactive metabolites identified in this work.”
In addition, from the abstract of a review (Monks et al. Current Drug Metab
2002): Quinones are ubiquitous in nature and constitute an important class of naturally occurring
compounds found in plants, fungi and bacteria… For example, the quinones of polycyclic aromatic
hydrocarbons are prevalent as environmental contaminants and provide a major source of current
human exposure to quinones. ... . Quinones are oxidants and electrophiles, and the relative
contribution of these properties to quinone toxicity is influenced by chemical structure,
in particular substituent effects.

19. All roads lead to Rome…or to quinoids (1)
From phenols  diphenols  quinones
When R= X-H the formation of a phenol or aminophenol is facilitated.
Even more facilitation….
Real drug examples exist
N
H
F
R
O
N
H
F
R
N
O
R
- HF
O
X
H
OH
X
O
X
OH
X
H
X = O,N
1,4-elimi-
nation
Oxid.
Rearr.
O
R OH
R
O
ALK
R
OH
OH
R
O
O
R
OH
OH
Nu R
O
OH
Me
R
Nu
Oxid. Oxid.
COMT
19

20. All roads lead to Rome…or to quinoids (2)
Quinone methides (quinomethanes) and quinone-imine methides.
Thompson et al. studied the phenol below (Toxicology 2001, 160, 197).
OH
O
S
O
O
O
[O,N]
H
H
[N,O]
[O,N]
O
H
H
- H2O
Oxid.
O
H O
O
H
O
H
When the benzylic alcohol forms
a sulfate (via SULT enzymes)
the elimination is even faster
The sulfates of the
corresponding 4-
alkoxy-benzylic
alcohols would also
be quite reactive.
O
O
S
O
O
O
R
20

21. All roads lead to Rome…or to quinoids (3)
Spontaneous loss of HF gives rise to a reactive, toxic species (Thompson et al. 2000)
Merck cpd published in 2005.
Decomposes to a carboxylic acid
on standing in a water solution
Order of events can be different (Kalgutkar et al. DMD 2007)
The example also shows that the leaving group can be a ”phenol”
Lefluonomide is a licensed
rheumatoid arthritis drug.
Instability due to isoxazole
ring opening dominates. No
reports of imine-methide
formation.
OH
F
F
F
O
F
F
- HF
N
H
O N
O
O
H
F
F F
F
N
N
H
F
O
O
F
N
H
N N
N
O
Cl
N
N
O
Cl
OH
R
Cl
O
Cyp
N
N
O
R
21

22. 22
Paracetamol can be directly oxidised to a reactive acetylated quinoneimine
Massive amounts of NAPQI will
exhaust GSH reserves
N
O
O
N
O
O
S
R
N
H
O
OH
S
R
N
H
O
OH
R-SH
Ox. Proton
shifts
NAPQ
Well-known quinoid-forming motifs of real drugs
Kassahun, K. Studies on the Metabolism of Troglitazone to
Reactive Intermediates in Vitro and in Vivo. Chem Res Toxicol
2001, 14, 62
O
O
H
O
S
N
H
O
O
O
O
O
S
N
H
O
O
O
O
H
GS
R
The thiazolidine ring might also
entail RM problems. But these are
not significant in low-dose
rosiglitazone (Avandia®, GSK) and
pioglitazone (Actos®, Lilly).
Troglitazone - withdrawn from the market.

23. 23
 Oxidation of heteroaromatics
 Acyl glucuronides (AGs) and acyl-CoA as
RMs
 Special case – the antiepileptic felbamate
 Formation of acyl halides (halothane)
A few other mechanisms of RM formation are
shown on the following four slides

24. 24
Heteroaromatics can also cause problems
 Thiophenes form epoxide and/or S-oxides (tienilic acid, a
diuretic drug, is a classic example; withdrawn 1982)
– The epoxide can also hydrolyse and ring-open
– Simple thiophenes largely abandoned within AZ
 Thiazoles can also cause problems
S
O
O COOH
Cl
Cl
S
+
R
O
S R
Nu
S R
O
S R
Nu
S R
Nu(p450
)
O
H
NuH
Add.-Elim.
NuH
Tienilic acid
+
O
S
N
H
Duloxetine (Cymbalta®)
does not appear to
show RM tox problems.
Daily dose is 60 mg.
Thiabendazole (an
anthelmintic), given
1-3 g/day shortterm
N
H
N
S
N
N
H
N
O
O S
NH2
H
+
P450

25.  Invoked mechanisms:
– Direct acylation (of amino groups)
– In theory, the acyl glycoside can isomerize by
acyl migration to expose a free aldehyde
(semiacetal) which can react with amines and
rearrange further.
 Rare proven cases. Benzoic acids don’t have AG problems whereas
aryl acetic acids (many NSAIDs) might have
– Many NSAIDs withdrawn from the market because
of hepatotoxicity. Mechanism? Most stuctures
have other potential liabilities stemming
from aromatic substructures, e.g. zomepirac
25
Reviews: Skonberg et al. Exp Op DM Tox 4
(2008) 425.
Bailey & Dickinson. Chemico-Biological
Interactions 145 (2003) 117/137
Acyl glucuronides (AGs) and acyl-CoA as RMs
From AZ workshop 2007: “The poorly defined link
between acyl glucuronides and toxicity was considered not to reflect evidence of
absence (of such a link), but rather absence of evidence (of such a link).”
Zomepirac,
withdrawn 1984
or
O
OH
OH
O
H
O
O
O
O
R R
O
N
H
R1
R1-NH2
R S
O
CoA
O
R
O
O
N
H
O
H
OH
O
O
Prot
O
N
OH
O
Cl

26. O
O
NH2
O
N
H2 O
O H
O
N
H2
O
O
O
N
H2 O
H O H
O
NH
O
O
H
N
H
N
Alb
O
N
N
Alb
H
Esterases
Alcohol
dehydro-
genase
Form ed via spon-
taneous loss of
carbam ic acid
26
Special case – the antiepileptic felbamate
Mechanism
Reaction of the isolated hemiaminal 1 with albumin
(Alb) was studied by Roller et al. in Chem Res Tox
2005, 15, 815. They concluded that conjugate
addition mainly goes via a histidine residue.
1
Within a year of its release in 1993
• 34 cases of aplastic anemia resulting in 13 deaths (Incidence rate 1:4800 – 1:37000)
• 23 cases of hepatotoxicity resulting in 5 deaths (Incidence rate 1:18000 – 1:25000
Black box warning (severe restriction in use)
• thousands of patients estimated to be on drug
Note
No glutathione
conjugates in liver
microsomes and human
hepatocytes.
No covalent binding to
liver microsomes and
human hepatocytes.

27. 27
Volatile anaesthetics and hepatotoxicity
Halothane – introduced1956,
“Delayed” liver injury in ~1: 3000 patients who receive multiple exposures,
and liver failure in ~1: 30,000
Enflurane - introduced in UK in 1981
“Delayed” liver injury in ~1: 100,000 patients who receive multiple exposures
Isoflurane - introduced in UK in 1984
Very rare case reports of “Delayed” liver injury, ~ <1: 100,000 patients who
receive multiple exposures
Sevoflurane - introduced in 1990, initially in Japan
Currently one of the most widely prescribed volatile anaesthetics in developed
nations. Rare case reports of “delayed” liver injury, from Japanese literature;
Desflurane - introduced 1956
Currently one of the most widely prescribed volatile anaesthetics in
developed nations. A few isolated case reports of “delayed” liver injury
F C C
F
F
Br
H
Cl
F C C
F
F
O
Cl
F C C
F
F
O
Protein
CYP 2E1
Halothane TFA-Cl TFA-protein
Mechanism of
halothane
activation

28. 28
Resources on reactive metabolites
 Literature reviews (see comprehensive list at awametox.com ), for
example
– Kalgutkar et al. (Pfizer), have written many reviews; latest one from 2019
– A. Claesson & A. Minidis, Chem. Res. Toxicol. 2018.
 Databases etc.
– SpotRM is a new application (2020). Read more at awametox.com and next slide.
– Lhasa Limited and MultiCASE are providers of computational tools on software
and knowledge.
– Major chemistry databases containing drugs & data: ChemPub, ChEMBLdb,
Chemspider.
– Drug metabolism predictive tools (MetaSite, MetaPrint2D, Meta-PC, and more): see
‘Directory of computer-aided Drug Design tools’ (ADME Toxicity)

29. SpotRM is a new* (Sept 2020) tool that helps you avoid the
test substances that have issues regarding reactive
metabolites
© 2012-2021 Awametox AB, Sweden. Contact: info@awametox.com
“SpotRM collects extensive knowledge in a format that allows quick access to
the original literature. When used frequently, you will quickly gain an
understanding why and how misdirected metabolism can be a grave problem.
Whenever possible, guidance to avoid or replace the particular structural alert is
given. The basis of our selection of alerts is reviewed in a Perspective paper: A.
Claesson & A. Minidis, Chem. Res. Toxicol. 2018. The Scope page provides
more background discussions.”
* This SpotRM app is quite different from the one that appeared briefly on the web between 2012-2015.