4,4'-Methylenebis(o-toluidine)

4,4'-Methylenebis(o-toluidine)



Associated High Confidence AOPs
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Associated AOPs with Level of Relevance 1
AOPs with at least 1 KE associated with chemical, where the KE(s) are neither MIE nor AO
AOP Identifier AOP Title AO Classification OECD Status Coverage Score KE Identifier KE Name
AOP:12Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in agingNervous System Disease; Developmental Disorder Of Mental HealthWPHA/WNT Endorsed0.12KE:55
Increase, Cell injury/death
AOP:13Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilitiesDevelopmental Disorder Of Mental HealthWPHA/WNT Endorsed0.1KE:55
Increase, Cell injury/death
AOP:15Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutationsGenetic DiseaseWPHA/WNT Endorsed0.25KE:155
Inadequate DNA repair
AOP:17Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memoryDevelopmental Disorder Of Mental HealthWPHA/WNT Endorsed0.1KE:55
Increase, Cell injury/death
AOP:27Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)Gastrointestinal System DiseaseUnder Development0.12KE:288
Activation of specific nuclear receptors, Transcriptional change
AOP:38Protein Alkylation leading to Liver FibrosisGastrointestinal System DiseaseWPHA/WNT Endorsed0.14KE:55
Increase, Cell injury/death
AOP:48Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.Developmental Disorder Of Mental HealthWPHA/WNT Endorsed0.11KE:55
Increase, Cell injury/death
AOP:58NR1I3 (CAR) suppression leading to hepatic steatosisGastrointestinal System Disease; Inherited Metabolic Disorder-0.06KE:457
Activation, SREBF1
AOP:62AKT2 activation leading to hepatic steatosisGastrointestinal System Disease; Inherited Metabolic Disorder-0.25KE:457
Activation, SREBF1
AOP:112Increased dopaminergic activity leading to endometrial adenocarcinomas (in Wistar rat)Reproductive System Disease; Cancer-0.17KE:111
Agonism, Estrogen receptor
AOP:131Aryl hydrocarbon receptor activation leading to uroporphyriaInherited Metabolic DisorderWPHA/WNT Endorsed0.17KE:850
Induction, CYP1A2/CYP1A5
AOP:136Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal TumorsBenign Neoplasm; Respiratory System DiseaseUnder Review0.14KE:768
Increase, Cytotoxicity
AOP:139Alkylation of DNA leading to cancer 1Cancer-0.25KE:155
Inadequate DNA repair
AOP:144Endocytic lysosomal uptake leading to liver fibrosisGastrointestinal System DiseaseUnder Review0.22KE:1494
Leukocyte recruitment/activation
KE:55
Increase, Cell injury/death
AOP:167Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.Reproductive System Disease; Cancer-0.14KE:1065
Activation, estrogen receptor alpha
AOP:173Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosisMusculoskeletal System Disease; Respiratory System DiseaseWPHA/WNT Endorsed0.12KE:1497
Increased, recruitment of inflammatory cells
AOP:194Hepatic nuclear receptor activation leading to altered amphibian metamorphosisUnclassified-0.17KE:295
Induction, Upregulation of glucuronyltransferase activity
AOP:209Perturbation of cholesterol and glutathione homeostasis leading to hepatotoxicity: Integrated multi-OMICS approach for building AOPGastrointestinal System Disease-0.12KE:1289
Perturbation of cholesterol
AOP:212Histone deacetylase inhibition leading to testicular atrophyReproductive System DiseaseWPHA/WNT Endorsed0.17KE:1505
Cell cycle, disrupted
AOP:264Uncoupling of oxidative phosphorylation leading to growth inhibition via ATP depletion associated cell deathUnclassifiedUnder Development0.25KE:55
Increase, Cell injury/death
AOP:265Uncoupling of oxidative phosphorylation leading to growth inhibition via increased cytosolic calciumUnclassifiedUnder Development0.25KE:55
Increase, Cell injury/death
AOP:266Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased Na-K ATPase activityUnclassifiedUnder Development0.17KE:55
Increase, Cell injury/death
AOP:268Uncoupling of oxidative phosphorylation leading to growth inhibition via mitochondrial swellingUnclassifiedUnder Development0.5KE:55
Increase, Cell injury/death
KE:2072
Increase, Mitochondrial swelling
AOP:272Deposition of energy leading to lung cancerCancerWPHA/WNT Endorsed0.14KE:155
Inadequate DNA repair
AOP:278IKK complex inhibition leading to liver injuryUnclassified-0.12KE:55
Increase, Cell injury/death
AOP:281Acetylcholinesterase Inhibition Leading to NeurodegenerationNervous System Disease-0.1KE:55
Increase, Cell injury/death
AOP:287Mitochondrial complex III antagonism leading to growth inhibition (2)Unclassified-0.25KE:1825
Increase, Cell death
AOP:288Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)Endocrine System Disease-0.12KE:1614
Decrease, androgen receptor activation
AOP:291Mitochondrial ATP synthase antagonism leading to growth inhibition (2)Unclassified-0.25KE:1825
Increase, Cell death
AOP:293Increased DNA damage leading to increased risk of breast cancerGenetic Disease; Thoracic Disease; CancerUnder Development0.11KE:1494
Leukocyte recruitment/activation
AOP:294Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancerGenetic Disease; Thoracic Disease; CancerUnder Development0.11KE:1494
Leukocyte recruitment/activation
AOP:296Oxidative DNA damage leading to chromosomal aberrations and mutationsGenetic Disease; Chromosomal DiseaseWPHA/WNT Endorsed0.2KE:155
Inadequate DNA repair
AOP:303Frustrated phagocytosis-induced lung cancerCancerUnder Development0.29KE:1669
Increased, DNA damage and mutation
KE:1497
Increased, recruitment of inflammatory cells
AOP:3055α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspringUnclassifiedUnder Development0.4KE:1614
Decrease, androgen receptor activation
KE:286
Altered, Transcription of genes by the androgen receptor
AOP:322Alkylation of DNA leading to reduced sperm countReproductive System Disease-0.2KE:155
Inadequate DNA repair
AOP:324Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and cell deathUnclassified-0.25KE:55
Increase, Cell injury/death
AOP:325Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell deathUnclassified-0.25KE:55
Increase, Cell injury/death
AOP:326Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell deathUnclassified-0.25KE:55
Increase, Cell injury/death
AOP:331Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and reduced cell proliferationUnclassified-0.17KE:1505
Cell cycle, disrupted
AOP:332Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferationUnclassified-0.2KE:1505
Cell cycle, disrupted
AOP:368Cytochrome oxidase inhibition leading to increased nasal lesionsUnclassified-0.33KE:1825
Increase, Cell death
AOP:392Decreased fibrinolysis and activated bradykinin system leading to hyperinflammationUnclassifiedUnder Development0.2KE:1497
Increased, recruitment of inflammatory cells
AOP:397Bulky DNA adducts leading to mutationsGenetic DiseaseUnder Development0.33KE:155
Inadequate DNA repair
AOP:409Frustrated phagocytosis leads to malignant mesotheliomaCancer-0.25KE:1669
Increased, DNA damage and mutation
KE:1497
Increased, recruitment of inflammatory cells
AOP:410GSK3beta inactivation leading to increased mortality via defects in developing inner earUnclassified-0.1KE:1825
Increase, Cell death
AOP:416Aryl hydrocarbon receptor activation leading to lung cancer through IL-6 toxicity pathwayCancer-0.17KE:1669
Increased, DNA damage and mutation
AOP:417Aryl hydrocarbon receptor activation leading to lung cancer through AHR-ARNT toxicity pathwayCancer-0.2KE:1669
Increased, DNA damage and mutation
AOP:418Aryl hydrocarbon receptor activation leading to impaired lung function through AHR-ARNT toxicity pathwayRespiratory System Disease-0.2KE:1825
Increase, Cell death
AOP:432Deposition of Energy by Ionizing Radiation leading to Acute Myeloid LeukemiaHematopoietic System Disease; Cancer-0.09KE:155
Inadequate DNA repair
AOP:446PM-related Adverse outcome pathway frameworks on various systemsRespiratory System Disease-0.05KE:1497
Increased, recruitment of inflammatory cells
AOP:451Interaction with lung resident cell membrane components leads to lung cancerCancer-0.22KE:1669
Increased, DNA damage and mutation
KE:1497
Increased, recruitment of inflammatory cells
AOP:458AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in MammalsCognitive Disorder-0.12KE:295
Induction, Upregulation of glucuronyltransferase activity
AOP:459AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in MammalsCognitive Disorder-0.11KE:850
Induction, CYP1A2/CYP1A5
AOP:464Calcium overload in dopaminergic neurons of the substantia nigra leading to parkinsonian motor deficitsNervous System Disease-0.05KE:1825
Increase, Cell death
AOP:465Alcohol dehydrogenase leading to reproductive dysfunctionUnclassified-0.12KE:748
Increased, Estrogen receptor (ER) activity
AOP:468Binding of SARS-CoV-2 to ACE2 leads to hyperinflammation (via cell death)Unclassified-0.25KE:1497
Increased, recruitment of inflammatory cells
KE:1825
Increase, Cell death
AOP:472DNA adduct formation leading to kidney failureUrinary System Disease-0.11KE:1825
Increase, Cell death
AOP:478Deposition of energy leading to occurrence of cataractsNervous System Disease; Monogenic DiseaseUnder Review0.1KE:155
Inadequate DNA repair
AOP:479Mitochondrial complexes inhibition leading to left ventricular function decrease via increased myocardial oxidative stressCardiovascular System Disease; Thoracic DiseaseUnder Development0.14KE:55
Increase, Cell injury/death
AOP:482Deposition of energy leading to occurrence of bone lossMusculoskeletal System DiseaseUnder Review0.14KE:1825
Increase, Cell death
AOP:490Co-activation of IP3R and RyR leads to reduced IQ through non-cholinergic mechanismsDevelopmental Disorder Of Mental Health-0.09KE:55
Increase, Cell injury/death
AOP:494AhR activation leading to liver fibrosisGastrointestinal System Disease-0.17KE:55
Increase, Cell injury/death
AOP:495Androgen receptor activation leading to prostate cancerReproductive System Disease; Cancer-0.11KE:286
Altered, Transcription of genes by the androgen receptor
AOP:496Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）Unclassified-0.1KE:286
Altered, Transcription of genes by the androgen receptor
AOP:510Demethylation of PPAR promotor leading to vascular disrupting effectsCardiovascular System Disease-0.1KE:2165
Activation of PPAR
AOP:530Endocytotic lysosomal uptake leads to intestinal barrier disruptionGastrointestinal System Disease-0.2KE:55
Increase, Cell injury/death
AOP:573Inhibition, cytochrome oxidase leads to Increased, pulmonary edemaRespiratory System Disease-0.33KE:1825
Increase, Cell death
AOP:574Inhibition, cytochrome oxidase leads to Loss of olfactory functionUnclassified-0.33KE:1825
Increase, Cell death

Associated AOPs with Level of Relevance 2
AOPs with at least 1 AO associated with chemical, and no associated MIE
AOP Identifier AOP Title AO Classification OECD Status Coverage Score KE Identifier KE Name
AOP:37PPARα activation leading to hepatocellular adenomas and carcinomas in rodentsCancer; Gastrointestinal System DiseaseUnder Development0.2KE:719
Increase, hepatocellular adenomas and carcinomas
AOP:43Disruption of VEGFR Signaling Leading to Developmental DefectsUnclassifiedWPHA/WNT Endorsed0.2KE:1001
Increased, Developmental Defects
AOP:107Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the ratCancer; Gastrointestinal System DiseaseUnder Review0.4KE:719
Increase, hepatocellular adenomas and carcinomas
KE:1214
Altered gene expression specific to CAR activation, Hepatocytes
AOP:108Inhibition of pyruvate dehydrogenase kinase leading to hepatocellular adenomas and carcinomas (in mouse and rat)Cancer; Gastrointestinal System Disease-0.33KE:768
Increase, Cytotoxicity
KE:719
Increase, hepatocellular adenomas and carcinomas
AOP:117Androgen receptor activation leading to hepatocellular adenomas and carcinomas (in mouse and rat)Cancer; Gastrointestinal System DiseaseUnder Development0.25KE:719
Increase, hepatocellular adenomas and carcinomas
AOP:118Chronic cytotoxicity leading to hepatocellular adenomas and carcinomas (in mouse and rat)Cancer; Gastrointestinal System Disease-0.25KE:719
Increase, hepatocellular adenomas and carcinomas
AOP:504SULT1E1 inhibition leading to uterine adenocarcinoma via increased estrogen availability at target organ levelUnclassified-0.33KE:1065
Activation, estrogen receptor alpha
AOP:561Aromatase induction leading to estrogen receptor alpha activation via increased estradiolUnclassified-0.2KE:1065
Activation, estrogen receptor alpha

Associated AOPs with Level of Relevance 3
AOPs with at least 1 MIE associated with chemical, and no associated AO
AOP Identifier AOP Title AO Classification OECD Status Coverage Score KE Identifier KE Name
AOP:8Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in MammalsNervous System DiseaseUnder Development0.22KE:295
Induction, Upregulation of glucuronyltransferase activity
KE:239
Activation, Pregnane-X receptor, NR1l2
AOP:19Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)Reproductive System Disease-0.4KE:26
Antagonism, Androgen receptor
KE:286
Altered, Transcription of genes by the androgen receptor
AOP:30Estrogen receptor antagonism leading to reproductive dysfunctionUnclassifiedUnder Review0.17KE:112
Antagonism, Estrogen receptor
AOP:42Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in MammalsCognitive DisorderWPHA/WNT Endorsed0.12KE:279
Thyroperoxidase, Inhibition
AOP:111Decrease in androgen receptor activity leading to Leydig cell tumors (in rat)Cancer; Reproductive System Disease-0.2KE:1614
Decrease, androgen receptor activation
AOP:119Inhibition of thyroid peroxidase leading to follicular cell adenomas and carcinomas (in rat and mouse)Cancer; Endocrine System Disease-0.14KE:279
Thyroperoxidase, Inhibition
AOP:159Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflationUnclassifiedWPHA/WNT Endorsed0.12KE:279
Thyroperoxidase, Inhibition
AOP:175Thyroperoxidase inhibition leading to altered amphibian metamorphosisUnclassified-0.25KE:279
Thyroperoxidase, Inhibition
AOP:271Inhibition of thyroid peroxidase leading to impaired fertility in fishUnclassifiedUnder Development0.2KE:279
Thyroperoxidase, Inhibition
AOP:306Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspringUnclassifiedUnder Development0.75KE:1614
Decrease, androgen receptor activation
KE:26
Antagonism, Androgen receptor
KE:286
Altered, Transcription of genes by the androgen receptor
AOP:314Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)Immune System Disease; Musculoskeletal System DiseaseUnder Development0.2KE:1710
Binding to estrogen receptor (ER)-α in immune cells
AOP:344Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspringUnclassifiedUnder Development0.75KE:1614
Decrease, androgen receptor activation
KE:26
Antagonism, Androgen receptor
KE:286
Altered, Transcription of genes by the androgen receptor
AOP:345Androgen receptor (AR) antagonism leading to decreased fertility in femalesEndocrine System Disease; Reproductive System Disease; Reproductive System DiseaseUnder Development0.5KE:1614
Decrease, androgen receptor activation
KE:26
Antagonism, Androgen receptor
KE:286
Altered, Transcription of genes by the androgen receptor
AOP:363Thyroperoxidase inhibition leading to altered visual function via altered retinal layer structureUnclassifiedUnder Review0.12KE:279
Thyroperoxidase, Inhibition
AOP:364Thyroperoxidase inhibition leading to altered visual function via decreased eye sizeUnclassifiedUnder Development0.12KE:279
Thyroperoxidase, Inhibition
AOP:365Thyroperoxidase inhibition leading to altered visual function via altered photoreceptor patterningUnclassifiedUnder Development0.12KE:279
Thyroperoxidase, Inhibition
AOP:372Androgen receptor antagonism leading to testicular cancerEndocrine System Disease; Reproductive System Disease; Cancer-0.6KE:1614
Decrease, androgen receptor activation
KE:26
Antagonism, Androgen receptor
KE:286
Altered, Transcription of genes by the androgen receptor
AOP:440Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasiaBenign Neoplasm; Endocrine System Disease; Reproductive System Disease; Reproductive System Disease; Cancer; Endocrine System DiseaseUnder Development0.22KE:1973
Increased, estrogens
KE:1046
Suppression, Estrogen receptor (ER) activity
AOP:443DNA damage and mutations leading to Metastatic Breast CancerThoracic Disease; CancerUnder Development0.3KE:1669
Increased, DNA damage and mutation
KE:155
Inadequate DNA repair
KE:112
Antagonism, Estrogen receptor
AOP:445Estrogen Receptor Alpha Agonism leads to Impaired ReproductionReproductive System Disease-0.25KE:1987
Decreased, Androgen and Progestin
KE:1065
Activation, estrogen receptor alpha
AOP:477Androgen receptor (AR) antagonism leading to hypospadias in male (mammalian) offspringPhysical Disorder-0.67KE:1614
Decrease, androgen receptor activation
KE:26
Antagonism, Androgen receptor
AOP:493ERa inactivation alters AT expansion and functions and leads to insulin resistance and metabolically unhealthy obesityAcquired Metabolic Disease-0.2KE:2126
Estrogen receptor alpha inactivation
KE:1497
Increased, recruitment of inflammatory cells
AOP:497ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndromeInherited Metabolic Disorder; Disease Of Metabolism-0.12KE:2126
Estrogen receptor alpha inactivation
AOP:503Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulationReproductive System Disease; CancerUnder Review0.17KE:1065
Activation, estrogen receptor alpha
AOP:517Pregnane X Receptor (PXR) activation leads to liver steatosisGastrointestinal System Disease; Inherited Metabolic Disorder-0.2KE:239
Activation, Pregnane-X receptor, NR1l2
AOP:525Reduced oligodendrocyte differentiation during neurodevelopment leading to impaired learning and memoryDevelopmental Disorder Of Mental Health-0.23KE:2115
Altered, cholesterol metabolism
KE:2220
Antagonism, Glucocorticoid hormone receptor
KE:2217
Binding of antagonist to glucocorticoid hormone receptor
AOP:536Estrogen receptor agonism leading to reduced survival and population growth due to renal failureUnclassified-0.17KE:111
Agonism, Estrogen receptor
AOP:537Estrogen receptor agonism leads to reduced fecundity via increased vitellogenin in the liverUnclassified-0.2KE:111
Agonism, Estrogen receptor
AOP:545Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased cholesterol synthesisUnclassified-0.2KE:239
Activation, Pregnane-X receptor, NR1l2
AOP:548Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased PCSK9 protein expressionUnclassified-0.2KE:239
Activation, Pregnane-X receptor, NR1l2

No associated AOPs with Level of Relevance 5
Glossary of Terms
AOP
Adverse Outcome Pathway
MIE
Molecular Initiating Event
KE
Key Event
AO
Adverse Outcome
Coverage score
The fraction of KEs within the AOP, that are mapped to the chemical-associated toxicological endpoints
Level of relevance
Qualitative rank based on the kind of associated KEs within the corresponding AOP
AO classification
The disease category corresponding to the AO in the AOP obtained from Disease Ontology
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TICToK is a knowledgebase of chemicals found in tattoo inks, compiled from publicly available regulatory and scientific resources. The chemical classifications presented in this knowledgebase are derived from multiple publicly available resources and are provided solely for informational purposes, and they are neither authoritative nor binding. The chemical-AOP mappings compiled in this knowledgebase serve as plausible hypotheses for research, and further experimental validation is required to definitively establish these potential toxicity mechanisms. The authors bear no responsibility for any errors, omissions, or inconsistencies originating from these external sources. Users are advised to exercise independent judgment when interpreting chemical classifications and any other data provided in this resource. Importantly, our sole goal to build this resource on tattoo ink chemicals is to enable future basic research on this topic, and it does not necessarily reflect the views or objectives of our employers or funders.