{"text_format":"1","workbook":"xlsx","n_sheets":18,"sheets":["Instructions","LookUp","LinkAB","LinkYZMammals","LinkYZFish","LinkYZAmphibian","LinkYZAvian","LinkInVitro","Interpretation","Data","Data summary","LoE females AOs","LoE males AOs","LoE in vitro mechanistic","LoE in vivo mechanistic","LoE other endocrine organs","LoE target organ toxicity","LoE systemic toxicity"],"not_rendered":{"charts":0,"images":0,"macros":1,"external_links":0,"defined_names":22,"comments":0,"pivot_tables":0},"unopened":[],"bounds":{"document_bytes":16777216,"sheet_cells":100000,"rows_first":2000,"rows_last":500,"rows_between":2000,"halvings":0,"cell_chars":16384,"cell_head_chars":4096},"cells_cut":0,"cells_raw":0,"read":"row_number_cap","date_system":"1900"}

{"sheet":"Instructions","index":0,"n_rows":4,"n_cols":14,"rows_kept":4,"cut":false,"hidden":true,"merged":[]}
["Instructions of use",null,null,null,null,null,null,null,null,null,null,null,"OLD","NEW"]
[null,null,null,null,null,null,null,null,null,null,null,"names management rules",70,27]
[null,"New occurrences on Y column"]
[null,"Add a sheet and name it as \"LinkYZnew"]

{"sheet":"LookUp","index":1,"n_rows":19,"n_cols":9,"rows_kept":19,"cut":false,"hidden":true,"merged":[]}
["LookUp Column","L","N","O","S","U","V","AD"]
["Header","Sex (administration)","Route of administration","Method of administration","Dose unit","Duration unit","Generation/Life stage","Effect direction","Relevance"]
[null,"M","Oral","Feed","mg/kg bw/day","Minutes","Adult","Increase","Yes"]
[null,"F","Inhalation","Gavage/Intubation","mg/L water","Hours","Adult (P1)","Decrease","No"]
[null,"M + F","Dermal","Whole-Body","mg/L","Days","Adult (F0)","Change","N/A"]
[null,null,"Direct","Capsule","µg ai/L","Weeks","Adult (F1)","Induction"]
[null,null,"Uptake from water","Water","Molar","Months","Adult (F2)","No effect"]
[null,null,"Uptake from the medium (in vitro)","Topical","ppm","Years","Adult (F0+F1)"]
[null,null,"[Not in list]","Not specified","µM",null,"Offspring (F1)"]
[null,null,null,"Subcutaneous","other",null,"Offspring (F2)"]
[null,null,null,"Intravenous",null,null,"Offspring (F3)"]
[null,null,null,"Nose only",null,null,"Offspring (F1+F2)"]
[null,null,null,"[Not in list]",null,null,"Fetus"]
[null,null,null,null,null,null,"Embryo"]
[null,null,null,null,null,null,"Larval"]
[null,null,null,null,null,null,"Juvenile"]
[null,null,null,null,null,null,"Tadpole"]
[null,null,null,null,null,null,"Eggs"]
[null,null,null,null,null,null,"[Not in list]"]

{"sheet":"LinkAB","index":2,"n_rows":32,"n_cols":15,"rows_kept":32,"cut":false,"hidden":true,"merged":[]}
["Column A","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle","Column B Study principle"]
["TypeOfToxicity","Mammals","Fish","Amphibian","Avian","InVitroEstrogen","InVitroAndrogen","InVitroThyroid","InVitroSteroidogenesis","InVitroToxCast Estrogen","InVitroToxCast Androgen","InVitroToxCast Thyroid","InVitroToxCast Steroidogenesis","InVitroHepatocytes","InVitroGeneral"]
[null,"Adult male assay","Fish short-term reproduction assay","Amphibian metamorphosis assay","Avian reproduction test","ER Binding Assay","AR Binding Assay","TR binding assay","H295R steroidogenesis assay","ToxCast ER prediction model","ToxCast AR prediction model","ATG_THRa1_TRANS_up","NVS_ADME_hCYP19A1","In vitro hepatocytes","In vitro method (general)"]
[null,"Carcinogenicity","21-day fish assay","Xenopus embryonic thyroid signalling assay XETA","US EPA avian two-generation study","Stably Transfected Human ERα Transcriptional Activation Assay (ER STTA)","Stably Transfected Human AR Transactivation Assay (AR STTA)","Other TR in vitro assay","Aromatase Assay","NVS_NR_bER","ATG_AR_TRANS_up","NVS_NR_hTRa","TOX21_Aromatase_Inhibition"]
[null,"Chronic toxicity","Androgenised female stickleback screen","Larval amphibian growth and development assay","Avian Not il list","BG1Luc Estrogen Receptor Transactivation Assay","Other AR in vitro assay",null,"Other Steroidogenesis in vitro assay","NVS_NR_hER","NVS_NR_cAR","Tox21_TR_LUC_GH3_Agonist","CEETOX_H295R_11DCORT_dn"]
[null,"Combined chronic toxicity/carcinogenicity studies","EASZY assay","Amphibian Not il list",null,"Other ER in vitro assay",null,null,null,"NVS_NR_mERa","NVS_NR_hAR","Tox21_TR_LUC_GH3_Antagonist","CEETOX_H295R_OHPREG_dn"]
[null,"Combined\nrepeated dose toxicity study with the reproduction/developmental toxicity screening test","Juvenile medaka anti-androgen screening assay",null,null,null,null,null,null,"OT_ER_ERaERa_0480","NVS_NR_rAR",null,"CEETOX_H295R_OHPREG_up"]
[null,"Developmental neurotoxicity study","Rapid androgen disruption adverse outcome reporter assay",null,null,null,null,null,null,"OT_ER_ERaERa_1440","OT_AR_ARELUC_AG_1440",null,"CEETOX_H295R_OHPROG_dn"]
[null,"Extended one-generation reproductive toxicity study","Fish sexual development test",null,null,null,null,null,null,"OT_ER_ERaERb_048","OT_AR_ARSRC1_0480",null,"CEETOX_H295R_ANDR_dn"]
[null,"Female pubertal assay (PP Female Assay)","Medaka extended one-generation reproduction test",null,null,null,null,null,null,"OT_ER_ERaERb_1440","OT_AR_ARSRC1_0960",null,"CEETOX_H295R_CORTISOL_dn"]
[null,"Fertility (Segment I)","Fish life cycle toxicity test",null,null,null,null,null,null,"OT_ER_ERbERb_0480","Tox21_AR_BLA_Agonist_ratio",null,"CEETOX_H295R_DOC_dn"]
[null,"Hershberger assay","Fish reproduction partial lifecycle test",null,null,null,null,null,null,"OT_ER_ERbERb_1440","Tox21_AR_BLA_Antagonist_ratio",null,"CEETOX_H295R_ESTRADIOL_dn"]
[null,"Male pubertal assay (PP Male Assay)","Fish early life stage toxicity test",null,null,null,null,null,null,"OT_ERa_EREGFP_0120","Tox21_AR_LUC_MDAKB2_Agonist",null,"CEETOX_H295R_ESTRONE_dn"]
[null,"Multigenerational reproductive toxicity","Fish Not il list",null,null,null,null,null,null,"OT_ERa_EREGFP_0480","Tox21_AR_LUC_MDAKB2_Antagonist",null,"CEETOX_H295R_PROG_dn"]
[null,"One-generation reproduction toxicity study",null,null,null,null,null,null,null,"ATG_ERa_TRANS_up",null,null,"CEETOX_H295R_PROG_up"]
[null,"Peripubertal male and female assays",null,null,null,null,null,null,null,"ATG_ERE_CIS_up",null,null,"CEETOX_H295R_TESTO_dn"]
[null,"Prenatal developmental toxicity study",null,null,null,null,null,null,null,"Tox21_ERa_BLA_Agonist_ratio"]
[null,"Repeated dose 28-day oral toxicity study in non-rodents",null,null,null,null,null,null,null,"Tox21_ERa_LUC_BG1_Agonist"]
[null,"Repeated dose 28-day oral toxicity study in rodents",null,null,null,null,null,null,null,"ACEA_T47D_80 h"]
[null,"Repeated dose 90-day oral toxicity study in non-rodents",null,null,null,null,null,null,null,"Tox21_ERa_BLA_Antagonist_ratio"]
[null,"Repeated dose 90-day oral toxicity study in rodents",null,null,null,null,null,null,null,"Tox21_ERa_LUC_BG1_Antagonist"]
[null,"Repeated dose dermal toxicity"]
[null,"Reproduction/developmental toxicity screening test"]
[null,"Subacute inhalation toxicity"]
[null,"Subacute oral in non-rodent "]
[null,"Subacute oral in rodent "]
[null,"Subchronic oral toxicity in rodents"]
[null,"Subchronic \ninhalation toxicity: 90-day study"]
[null,"Subchronic dermal toxicity: 90-day study"]
[null,"Two-generation reproduction toxicity test"]
[null,"Uterotrophic assay"]
[null,"Mammals Not il list"]

{"sheet":"LinkYZMammals","index":3,"n_rows":51,"n_cols":9,"rows_kept":51,"cut":false,"hidden":true,"merged":[]}
["Column Y","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target"]
["Effect type","In life observation","Organ Weight","Organ histopathology","Reproductive","Developmental","Abnormalities","Clinical chemistry/hormones","No relevant effect observed"]
[null,"Body weight","Adrenals weight","Accessory sex organs histopathology","Age at balanopreputial separation","Auditory startle","Ano-Genital distance","Estradiol level","No relevant effect observed"]
[null,"Clinical chemistry and haematology","Adrenals weight (Hershberger)","Adrenals histopathology","Age at first estrus","Brain morphometric (quantitative) evaluation","Genital abnormalities","Follicle Stimulating Hormone (FSH) level"]
[null,"Clinical signs","Brain weight","Aorta histopathology","Age at Vaginal opening","Fetal development","Nipple Development","HDL/LDL ratio (considered T-mediated only in combination with other thyroid endpoints)"]
[null,"Food consumption","Coagulating gland weight","Bone histopathology","Dystocia","Functional observation battery","Presence of anomalies (external, visceral, skeletal","Luteinizing Hormone (LH) level"]
[null,"Mortality","Cowper's gland weight","Bone marrow histopathology","Estrus cyclicity","Learning and memory in offspring","[Not in list]","Steroidogenesis (genes/enzyme changes)"]
[null,"[Not in list]","Cowpers glands weight (Hershberger)","Brain histopathology examination","Fertility (mammals)","Litter/pup weight",null,"T3 and T4 level"]
[null,null,"Epididymis weight","Cervix histopathology","Gestation length","Motor activity",null,"Testosterone level"]
[null,null,"Epididymis weight (Hershberger)","Coagulating gland histopathology","Litter size","Motor and sensory function",null,"Thyroid-stimulating hormone level (TSH)"]
[null,null,"Glans penis weight","Colloid area (thyroid histopathology)","Litter viability","Pup development",null,"Thyroid-releasing hormone level (TRH)"]
[null,null,"Glans penis weight  (Hershberger)","Epididymis histopathology","Number of implantations, corpora lutea","[Not in list]",null,"Prolactin"]
[null,null,"Heart weight","Eyes histopathology","Number of live births",null,null,"Progesterone"]
[null,null,"Kidney weight","Follicular cell height (thyroid histopathology)","Number of ovarian follicles",null,null,"Cortisol"]
[null,null,"LABC weight","Gall bladder histopathology","Numbers of embryonic or foetal deaths and viable foetuses",null,null,"Androstenedione"]
[null,null,"LABC weight (Hershberger)","Heart histopathology","Post implantation loss",null,null,"Other hormones"]
[null,null,"Liver weight","Keratinisation and cornification of vagina","Pre implantation loss",null,null,"Nuclear receptor (in vivo)"]
[null,null,"Liver weight (Hershberger, considered T-mediated only in combination with other thyroid endpoints)","Keratinisation and cornification of vagina (UT assay)","Pup survival index",null,null,"CAR nuclear receptor (in vivo)"]
[null,null,"Liver weight (considered T-mediated only in combination with other thyroid endpoints)","Kidney histopathology","Reproduction",null,null,"PXR nuclear receptor (in vivo)"]
[null,null,"Ovary weight","Liver histopathology","Sex ratio",null,null,"PPAR nuclear receptor (in vivo)"]
[null,null,"Pituitary weight","Lung histopathology","Sperm morphology",null,null,"TSH receptor"]
[null,null,"Prostate weight","Lymph nodes histopathology","Sperm motility",null,null,"Phase I enzyme induction (in vivo)"]
[null,null,"Prostate weight (Hershberger)","Mammary gland histopathology (female)","Sperm numbers",null,null,"Phase II enzyme induction (in vivo)"]
[null,null,"Seminal vesicles weight","Mammary gland histopathology (male)","Time to mating",null,null,"Thyroid hormone clearance"]
[null,null,"Seminal vesicles weight (Hershberger)","Oesophagus histopathology","Vaginal opening (UT assay)",null,null,"Iodine uptake"]
[null,null,"Spleen weight","Ovary histopathology","[Not in list]",null,null,"Thyroperoxidase activity (TPO)"]
[null,null,"Testis weight","Oviduct histopathology",null,null,null,"Sodium-iodide symporter (NIS)"]
[null,null,"Testis weight (Hershberger)","Pancreas histopathology",null,null,null,"Thyroxin-binding protein (TBG)"]
[null,null,"Thymus weight","Peripheral nerve histopathology",null,null,null,"Transthyretin (TTR)"]
[null,null,"Thyroid weight","Pituitary histopathology",null,null,null,"Deiodination enzyme activity"]
[null,null,"Uterus weight (UT assay)","Proliferation of endometrial epithelium",null,null,null,"[Not in list]"]
[null,null,"Uterus weight (with cervix)","Proliferation of endometrial epithelium (UT assay)"]
[null,null,"[Not in list]","Prostate histopathology (with seminal vesicles and coagulating glands)"]
[null,null,null,"Salivary glands histopathology"]
[null,null,null,"Seminal vesicles histopathology"]
[null,null,null,"Skeletal muscle histopathology"]
[null,null,null,"Skin histopathology"]
[null,null,null,"Small and large intestines histopathology"]
[null,null,null,"Spinal cord histopathology"]
[null,null,null,"Spleen histopathology"]
[null,null,null,"Stomach histopathology"]
[null,null,null,"Testis histopathology"]
[null,null,null,"Thymus histopathology"]
[null,null,null,"Thyroid histopathology"]
[null,null,null,"Trachea histopathology"]
[null,null,null,"Urinary bladder histopathology"]
[null,null,null,"Uterus histopathology (UT assay)"]
[null,null,null,"Uterus histopathology (with cervix)"]
[null,null,null,"Vagina histopathology"]
[null,null,null,"Vaginal smears"]
[null,null,null,"[Not in list]"]

{"sheet":"LinkYZFish","index":4,"n_rows":13,"n_cols":7,"rows_kept":13,"cut":false,"hidden":true,"merged":[]}
["Column Y","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target"]
["Effect type","In life observation","Organ histopathology","Reproductive","Abnormalities","Clinical chemistry/hormones","No relevant effect observed"]
[null,"Behaviour (fish)","Kidney histopathology (fish)","Embryo time-to-hatch","Morphological abnormalities","Estradiol level","No relevant effect observed"]
[null,"Body weight (fish)","Liver histopathology (fish)","Gonado-somatic index",null,"Levels of thyroid hormones"]
[null,"Hepatosomatic index","Specific gonad histopathology","Hatching success",null,"Spiggin"]
[null,"Larval survival and length","[Not in list]","Male 2nd sex characteristics in females",null,"T3 and T4 level"]
[null,"Length (fish)",null,"Male 2nd sex characteristics in males",null,"Testosterone level"]
[null,"Mortality",null,"Reproduction (fecundity, fertility)",null,"Vitellogenin (VTG) in females"]
[null,"Survival (fish)",null,"Sex ratio (Female biased) ",null,"Vitellogenin (VTG) in males"]
[null,"Survival of embryos",null,"Sex ratio (Male biased) ",null,"[Not in list]"]
[null,"[Not in list]",null,"Time to maturity (time to first spawn)"]
[null,null,null,"Transcriptional activity of cyp19a1b"]
[null,null,null,"[Not in list]"]

{"sheet":"LinkYZAmphibian","index":5,"n_rows":7,"n_cols":9,"rows_kept":7,"cut":false,"hidden":true,"merged":[]}
["Column Y","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target"]
["Effect type","In life observation","Organ Weight","Organ histopathology","Reproductive","Developmental","Abnormalities","Clinical chemistry/hormones","No relevant effect observed"]
[null,"Behaviour (amphibian)","Liver weight (liver-somatic index;) (amphibian)","Histopathology (gonad, reproductive ducts)","Sex ratio (phenotypic [gonad histology], genetic)","Developmental stage","Malformations","Plasma level of vitellogenin","No relevant effect observed"]
[null,"Body weight (amphibian)","[Not in list]","Kidney histopathology (amphibian)",null,"Hind limb length","[Not in list]","Transcriptional activity of THbZIP"]
[null,"Mortality (amphibian)",null,"Liver histopathology (amphibian)",null,"Time to metamorphosis (NF stage 62)",null,"[Not in list]"]
[null,"Snout-vent length/growth",null,"Thyroid histopathology (amphibian)",null,"[Not in list]"]
[null,"[Not in list]",null,"[Not in list]"]

{"sheet":"LinkYZAvian","index":6,"n_rows":17,"n_cols":6,"rows_kept":17,"cut":false,"hidden":true,"merged":[]}
["Column Y","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target"]
["Effect type","In life observation","Organ histopathology","Reproductive","Clinical chemistry/hormones","No relevant effect observed"]
[null,"Body weight (bird)","Gonad histopathology (bird)","Cracked eggs","Estradiol, testosterone and thyroid hormone measurements (egg yolk, adult, thyroid hormone from thyroid gland)","No relevant effect observed"]
[null,"Mortality","Gross pathology (bird)","Egg fertility (embryonic day 8)","[Not in list]"]
[null,"[Not in list]","Kidney histopathology (bird)","Egg production"]
[null,null,"Liver histopathology (bird)","Egg viability (% viable embryo of egg set)"]
[null,null,"Thyroid gland histopathology (bird)","Eggshell strength (newton)"]
[null,null,"[Not in list]","Eggshell thickness"]
[null,null,null,"Embryo viability (embryonic day 15)"]
[null,null,null,"Hatchability"]
[null,null,null,"No of 14 day-old survivors"]
[null,null,null,"Phenotypic and genotypic sex ratio"]
[null,null,null,"Survival (bird)"]
[null,null,null,"Time to female reproductive maturation (first egg production)"]
[null,null,null,"Time to male reproductive maturation (first foam production)"]
[null,null,null,"Viable embryos"]
[null,null,null,"[Not in list]"]

{"sheet":"LinkInVitro","index":7,"n_rows":38,"n_cols":13,"rows_kept":38,"cut":false,"hidden":true,"merged":[]}
["Column Y","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target","Column Z Effect target"]
["Effect type","Receptor binding","Receptor (trans)activation","Receptor dimerization","Cofactor Recruitment","DNA Binding","Enzyme inhibition","Proliferation","Steroidogenesis","Transport protein binding","Enzyme inhibition/induction","Hormones measurments","[Not in list]"]
[null,"Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","Estrogen receptor","No relevant effect observed"]
[null,"Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor","Estrogen related receptor"]
[null,"Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor","Androgen receptor"]
[null,"Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor","Thyroid receptor"]
[null,"Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)","Nuclear receptor (in vitro)"]
[null,"CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)","CAR nuclear receptor (in vitro)"]
[null,"PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)","PXR nuclear receptor (in vitro)"]
[null,"PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)","PPAR nuclear receptor (in vitro)"]
[null,"TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)","TSH receptor (in vitro)"]
[null,"Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis","Estradiol synthesis"]
[null,"Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis","Testosterone synthesis"]
[null,"CYP19","CYP19","CYP19","CYP19","CYP19","CYP19","CYP19","CYP19","CYP19","CYP19","CYP19"]
[null,"Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)","Steroidogenesis (genes/enzyme changes) (in vitro)"]
[null,"Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)","Estradiol level (in vitro)"]
[null,"Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)","Testosterone level (in vitro)"]
[null,"11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)","11-Deoxycortisol (in vitro)"]
[null,"17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)","17-alpha-hydroxypregnelone (in vitro)"]
[null,"17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)","17-alpha-hydroxyprogesterone (in vitro)"]
[null,"Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)","Androstenedione (in vitro)"]
[null,"Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)","Cortisol (in vitro)"]
[null,"11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)","11-Deoxycorticosterone (in vitro)"]
[null,"Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)","Estrone (in vitro)"]
[null,"Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)","Progesterone (in vitro)"]
[null,"T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)","T3 and T4 level (in vitro)"]
[null,"Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)","Thyroid-stimulating hormone level (TSH) (in vitro)"]
[null,"Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)","Other hormones (in vitro)"]
[null,"Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)","Phase I enzyme induction (in vitro)"]
[null,"Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)","Phase II enzyme induction (in vitro)"]
[null,"Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)","Thyroid hormone clearance (in vitro)"]
[null,"Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)","Thyroperoxidase activity (TPO) (in vitro)"]
[null,"Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)","Sodium-iodide symporter (NIS) (in vitro)"]
[null,"Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)","Thyroxin-binding protein (TBG) (in vitro)"]
[null,"Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)","Transthyretin (TTR) (in vitro)"]
[null,"Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)","Deiodination enzyme activity (in vitro)"]
[null,"Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation","Cellular proliferation"]
[null,"[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]","[Not in list]"]

{"sheet":"Interpretation","index":8,"n_rows":251,"n_cols":5,"rows_kept":251,"cut":false,"hidden":true,"merged":[]}
["Column A","Column Y","Column Z","Column AA","Indicative of"]
["Mammals","Abnormalities","Ano-Genital distance","EATS-mediated","E, A, S"]
["Mammals","Abnormalities","Genital abnormalities","EATS-mediated","E, A, S"]
["Mammals","Abnormalities","Nipple Development","EATS-mediated","A"]
["Mammals","Abnormalities","Presence of anomalies (external, visceral, skeletal","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Clinical chemistry","Estradiol level","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Follicle Stimulating Hormone (FSH) level","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Luteinizing Hormone (LH) level","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Steroidogenesis (genes/enzyme changes)","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","T3 and T4 level","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Testosterone level","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Thyroid-stimulating hormone level (TSH)","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Thyroid-releasing hormone level (TRH)","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Prolactin","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","Progesterone","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Cortisol","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Androstenedione","In vivo mechanistic","E, A, S"]
["Mammals","Clinical chemistry","Other hormones","In vivo mechanistic","_"]
["Mammals","Clinical chemistry","Nuclear receptor (in vivo)","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","CAR nuclear receptor (in vivo)","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","PXR nuclear receptor (in vivo)","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","PPAR nuclear receptor (in vivo)","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","TSH receptor","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Phase I enzyme induction (in vivo)","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","Phase II enzyme induction (in vivo)","In vivo mechanistic","E, A, T, S"]
["Mammals","Clinical chemistry","Thyroid hormone clearance","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Iodine uptake","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Thyroperoxidase activity (TPO)","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Sodium-iodide symporter (NIS)","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Thyroxin-binding protein (TBG)","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Transthyretin (TTR)","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","Deiodination enzyme activity","In vivo mechanistic","T"]
["Mammals","Clinical chemistry","HDL/LDL ratio (considered T-mediated only in combination with other thyroid endpoints)","EATS-mediated","T"]
["Mammals","Developmental","Auditory startle","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Brain morphometric (quantitative) evaluation","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Fetal development","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Functional observation battery","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Learning and memory in offspring","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Litter/pup weight","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Motor activity","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Motor and sensory function","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Developmental","Pup development","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ histopathology","Keratinisation and cornification of vagina (UT assay)","In vivo mechanistic","E"]
["Mammals","Organ histopathology","Proliferation of endometrial epithelium (UT assay)","In vivo mechanistic","E"]
["Mammals","Organ histopathology","Uterus histopathology (UT assay)","In vivo mechanistic","E"]
["Mammals","Organ histopathology","Accessory sex organs histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Cervix histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Coagulating gland histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Colloid area (thyroid histopathology)","EATS-mediated","T"]
["Mammals","Organ histopathology","Epididymis histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Follicular cell height (thyroid histopathology)","EATS-mediated","T"]
["Mammals","Organ histopathology","Mammary gland histopathology (male)","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Mammary gland histopathology (female)","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Ovary histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Oviduct histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Keratinisation and cornification of vagina","EATS-mediated","E"]
["Mammals","Organ histopathology","Proliferation of endometrial epithelium","EATS-mediated","E"]
["Mammals","Organ histopathology","Prostate histopathology (with seminal vesicles and coagulating glands)","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Seminal vesicles histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Testis histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Thyroid histopathology","EATS-mediated","T"]
["Mammals","Organ histopathology","Uterus histopathology (with cervix)","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Vagina histopathology","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Vaginal smears","EATS-mediated","E, A, S"]
["Mammals","Organ histopathology","Adrenals histopathology","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ histopathology","Brain histopathology examination","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ histopathology","Pituitary histopathology","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ histopathology","Aorta histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Bone histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Bone marrow histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Eyes histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Gall bladder histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Heart histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Kidney histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Liver histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Lung histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Lymph nodes histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Oesophagus histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Pancreas histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Peripheral nerve histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Salivary glands histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Skeletal muscle histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Skin histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Small and large intestines histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Spinal cord histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Spleen histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Stomach histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Thymus histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Trachea histopathology","Target organ toxicity","_"]
["Mammals","Organ histopathology","Urinary bladder histopathology","Target organ toxicity","_"]
["Mammals","Organ Weight","Adrenals weight (Hershberger)","In vivo mechanistic","N"]
["Mammals","Organ Weight","Cowpers glands weight (Hershberger)","In vivo mechanistic","A"]
["Mammals","Organ Weight","Epididymis weight (Hershberger)","In vivo mechanistic","E, A, S"]
["Mammals","Organ Weight","Glans penis weight  (Hershberger)","In vivo mechanistic","A"]
["Mammals","Organ Weight","LABC weight (Hershberger)","In vivo mechanistic","A"]
["Mammals","Organ Weight","Liver weight (Hershberger, considered T-mediated only in combination with other thyroid endpoints)","In vivo mechanistic","T"]
["Mammals","Organ Weight","Prostate weight (Hershberger)","In vivo mechanistic","A"]
["Mammals","Organ Weight","Seminal vesicles weight (Hershberger)","In vivo mechanistic","A"]
["Mammals","Organ Weight","Testis weight (Hershberger)","In vivo mechanistic","E, A, S"]
["Mammals","Organ Weight","Uterus weight (UT assay)","In vivo mechanistic","E, A"]
["Mammals","Organ Weight","Coagulating gland weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Cowper's gland weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Epididymis weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Glans penis weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","LABC weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Liver weight (considered T-mediated only in combination with other thyroid endpoints)","EATS-mediated","T"]
["Mammals","Organ Weight","Ovary weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Prostate weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Seminal vesicles weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Testis weight","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Thyroid weight","EATS-mediated","T"]
["Mammals","Organ Weight","Uterus weight (with cervix)","EATS-mediated","E, A, S"]
["Mammals","Organ Weight","Adrenals weight","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ Weight","Brain weight","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ Weight","Pituitary weight","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Organ Weight","Heart weight","Target organ toxicity","_"]
["Mammals","Organ Weight","Kidney weight","Target organ toxicity","_"]
["Mammals","Organ Weight","Liver weight","Target organ toxicity","_"]
["Mammals","Organ Weight","Spleen weight","Target organ toxicity","_"]
["Mammals","Organ Weight","Thymus weight","Target organ toxicity","_"]
["Mammals","Reproductive","Vaginal opening (UT assay)","In vivo mechanistic","E, A"]
["Mammals","Reproductive","Age at first estrus","EATS-mediated","E, A"]
["Mammals","Reproductive","Age at balanopreputial separation","EATS-mediated","E, A, S"]
["Mammals","Reproductive","Age at vaginal opening","EATS-mediated","E, A, S"]
["Mammals","Reproductive","Estrus cyclicity","EATS-mediated","E, A, S"]
["Mammals","Reproductive","Sperm morphology","EATS-mediated","E, A, S"]
["Mammals","Reproductive","Sperm motility","EATS-mediated","E, A, S"]
["Mammals","Reproductive","Sperm numbers","EATS-mediated","E, A, S"]
["Mammals","Reproductive","Dystocia","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Fertility (mammals)","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Gestation length","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Litter size","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Litter viability","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Number of implantations, corpora lutea","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Number of live births","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Numbers of embryonic or foetal deaths and viable foetuses","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Number of ovarian follicles","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Post implantation loss","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Pre implantation loss","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Pup survival index","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Reproduction","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Sex ratio","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","Reproductive","Time to mating","Sensitive to, but not diagnostic of, EATS","N"]
["Mammals","In life observation","Body weight","Systemic toxicity","_"]
["Mammals","In life observation","Clinical chemistry and haematology","Systemic toxicity","_"]
["Mammals","In life observation","Clinical signs","Systemic toxicity","_"]
["Mammals","In life observation","Food consumption","Systemic toxicity","_"]
["Mammals","In life observation","Mortality","Systemic toxicity","_"]
["Fish","Abnormalities","Morphological abnormalities","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Clinical chemistry","Vitellogenin (VTG) in females","In vivo mechanistic","E, A, S"]
["Fish","Clinical chemistry","Vitellogenin (VTG) in males","In vivo mechanistic","E, A, S"]
["Fish","Clinical chemistry","Spiggin","In vivo mechanistic","A"]
["Fish","Clinical chemistry","Estradiol level","In vivo mechanistic"]
["Fish","Clinical chemistry","Levels of thyroid hormones","In vivo mechanistic"]
["Fish","Clinical chemistry","T3 and T4 level","In vivo mechanistic"]
["Fish","Clinical chemistry","Testosterone level","In vivo mechanistic"]
["Fish","Clinical chemistry","Transcriptional activity of cyp19a1b","In vivo mechanistic","E"]
["Fish","Developmental","Behaviour (fish)","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Developmental","Length (fish)","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Organ histopathology","Specific gonad histopathology","EATS-mediated","E, A, S"]
["Fish","In life observation","Liver histopathology (fish)","Systemic toxicity","_"]
["Fish","In life observation","Kidney histopathology (fish)","Systemic toxicity","_"]
["Fish","In life observation","Body weight (fish)","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Reproductive","Male 2nd sex characteristics in females","EATS-mediated","A"]
["Fish","Reproductive","Male 2nd sex characteristics in males","EATS-mediated","E, A, S"]
["Fish","Reproductive","Sex ratio (Female biased) ","EATS-mediated","E, A"]
["Fish","Reproductive","Sex ratio (Male biased) ","EATS-mediated","E, A, S"]
["Fish","Reproductive","Gonado-somatic index","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Reproductive","Embryo time-to-hatch","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Reproductive","Reproduction (fecundity, fertility)","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","In life observation","Survival (fish)","Systemic toxicity","_"]
["Fish","Reproductive","Larval survival and length","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Reproductive","Survival of embryos","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Reproductive","Time to maturity (time to first spawn)","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","Reproductive","Hatching success","Sensitive to, but not diagnostic of, EATS","N"]
["Fish","In life observation","Hepatosomatic index","Systemic toxicity","_"]
["Fish","In life observation","Mortality","Systemic toxicity","_"]
["Amphibians","Abnormalities","Malformations","Sensitive to, but not diagnostic of, EATS","N"]
["Amphibians","Clinical chemistry","Plasma level of vitellogenin","In vivo mechanistic","E, A, S"]
["Amphibians","Clinical chemistry","Transcriptional activity of THbZIP","In vivo mechanistic","T"]
["Amphibians","Developmental","Hind limb length","EATS-mediated","T"]
["Amphibians","Developmental","Developmental stage","EATS-mediated","T"]
["Amphibians","Developmental","Time to metamorphosis (NF stage 62)","EATS-mediated","T"]
["Amphibians","Developmental","Snout-vent length/growth","Sensitive to, but not diagnostic of, EATS","N"]
["Amphibians","Developmental","Behaviour (amphibian)","Sensitive to, but not diagnostic of, EATS","N"]
["Amphibians","In life observation","Mortality (amphibian)","Systemic toxicity","_"]
["Amphibians","Organ histopathology","Thyroid histopathology (amphibian)","EATS-mediated","T"]
["Amphibians","Organ histopathology","Histopathology (gonad, reproductive ducts)","EATS-mediated","E, A"]
["Amphibians","In life observation","Liver histopathology (amphibian)","Systemic toxicity","_"]
["Amphibians","In life observation","Kidney histopathology (amphibian)","Systemic toxicity","_"]
["Amphibians","In life observation","Body weight (amphibian)","Sensitive to, but not diagnostic of, EATS","N"]
["Amphibians","Organ Weight","Liver weight (liver-somatic index;) (amphibian)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Clinical chemistry","Estradiol, testosterone and thyroid hormone measurements (egg yolk, adult, thyroid hormone from thyroid gland)","In vivo mechanistic","E, A, T, S"]
["Birds","Organ histopathology","Thyroid gland histopathology (bird)","EATS-mediated","T"]
["Birds","Organ histopathology","Gonad histopathology (bird)","EATS-mediated","E, A"]
["Birds","Organ histopathology","Gross pathology (bird)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","In life observation","Liver histopathology (bird)","Systemic toxicity","_"]
["Birds","In life observation","Kidney histopathology (bird)","Systemic toxicity","_"]
["Birds","In life observation","Body weight (bird)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Phenotypic and genotypic sex ratio","EATS-mediated","E, A"]
["Birds","Reproductive","Hatchability","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Egg fertility (embryonic day 8)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Eggshell thickness","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Eggshell strength (newton)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Egg viability (% viable embryo of egg set)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Embryo viability (embryonic day 15)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Egg production","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Cracked eggs","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","In life observation","Survival (bird)","Systemic toxicity","_"]
["Birds","Reproductive","Viable embryos","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","No of 14 day-old survivors","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Time to female reproductive maturation (first egg production)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","Reproductive","Time to male reproductive maturation (first foam production)","Sensitive to, but not diagnostic of, EATS","N"]
["Birds","In life observation","Mortality","Systemic toxicity","_"]
["In vitro",null,"Estrogen receptor","In vitro mechanistic","E"]
["In vitro",null,"Estrogen related receptor","In vitro mechanistic","E"]
["In vitro",null,"Androgen receptor","In vitro mechanistic","A"]
["In vitro",null,"Thyroid receptor","In vitro mechanistic","T"]
["In vitro",null,"Nuclear receptor (in vitro)","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"CAR nuclear receptor (in vitro)","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"PXR nuclear receptor (in vitro)","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"PPAR nuclear receptor (in vitro)","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"TSH receptor (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Estradiol synthesis","In vitro mechanistic","E, A, S"]
["In vitro",null,"Testosterone synthesis","In vitro mechanistic","E, A, S"]
["In vitro",null,"CYP19","In vitro mechanistic","S"]
["In vitro",null,"Steroidogenesis (genes/enzyme changes) (in vitro)","In vitro mechanistic","S"]
["In vitro",null,"Estradiol level (in vitro)","In vitro mechanistic","E"]
["In vitro",null,"Testosterone level (in vitro)","In vitro mechanistic","A"]
["In vitro",null,"T3 and T4 level (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Thyroid-stimulating hormone level (TSH) (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Other hormones (in vitro)","In vitro mechanistic","_"]
["In vitro",null,"Phase I enzyme induction (in vitro)","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"Phase II enzyme induction (in vitro)","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"Thyroid hormone clearance (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Thyroperoxidase activity (TPO) (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Sodium-iodide symporter (NIS) (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Thyroxin-binding protein (TBG) (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Transthyretin (TTR) (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Deiodination enzyme activity (in vitro)","In vitro mechanistic","T"]
["In vitro",null,"Cellular proliferation","In vitro mechanistic","E, A, T, S"]
["In vitro",null,"11-Deoxycortisol (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"17-alpha-hydroxypregnelone (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"17-alpha-hydroxyprogesterone (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"Androstenedione (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"Cortisol (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"11-Deoxycorticosterone (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"Estrone (in vitro)","In vitro mechanistic","E, A, S"]
["In vitro",null,"Progesterone (in vitro)","In vitro mechanistic","E, A, S"]
[null,null,"[Not in list]","[Not in list]"]
[null,null,"No relevant effect observed","No relevant effect observed"]

{"sheet":"Data","index":9,"n_rows":236,"n_cols":37,"rows_kept":236,"cut":false,"hidden":false,"merged":[],"read":"row_number_cap"}
["Compound: D4"]
["CAS: 556-67-2"]
["Comments:",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"E = Endpoints for estrogen-mediated activity"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"A = Endpoints for androgen-mediated activity"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"T = Endpoints for thyroid-related activity"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"S = Endpoints for steroidogenesis related activity"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"N = Endpoints potentially sensitive to, but not diagnostic of, EATS modalities"]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"_ = Endpoints related to target organ toxicity and systemic toxicity"]
[]
[]
["Type of toxicity","Study principle","Study ID Matrix","Study reference ID"," Study guideline (OECD/US EPA) or remarks","Source","Reference (citation)","Reporting date","Species","Strain or in vitro model","Animals/sex/group","Sex (administration)","Purity (%)","Route of administration","Method of administration","Doses tested","Lowest dose tested","Highest dose tested","Dose unit","Duration of exposure","Duration unit","Generation/Life stage","Sex (effect dose)","Lowest Effect dose","Effect type","Effect target","Effect classification","Effect description","Effect determination","Effect direction","NOAEL/NOEL/NOEC","LOAEL/LOEL/LOEC","Unit","Effect indicative of","Additional remarks","Relevance","Reliability"]
["InVitroEstrogen","Other ER in vitro assay",1,"Lee et al. 2015","In vitro assay","Open literature","Lee et al. 2015",2015,"Rat","GH3 cells","3 replicates",null,"Not reported","Uptake from the medium (in vitro)","[Not in list]","1.0 × 10−5 ","1.0 × 10−5 ","1.0 × 10−5 ","Molar",1,"Days","[Not in list]",null,"1.0 × 10−5 ","Receptor (trans)activation","[Not in list]",{"$f":"IF(Z12<>0,VLOOKUP(Z12,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Increased CaBP-9K (10-fold gene expression compared to control), decreased Erα (0.6-fold gene expression) and increased PR (1.5-fold gene expression) gene and protein expression. ","Expression levels relative to stable reference genes or proteins","Change",null,"1.0 × 10−5 ","Molar",{"$f":"IF(Z12<>0,VLOOKUP(Z12,Interpretation!$C:$E,3,FALSE),\"\")","v":0},"Direction of effects similar to effects of E2 exposure on CaBP-9K (E2 approx. 50-fold increase in gene expression compared to control), Erα (E2 approx. 0.7-fold gene expression compared to control) and PR (E2 approx. 4.5-fold increase in gene expression compared to control) gene and protein expression. Pre-incubation with ERα inhibitor ICI blocked the effects. Protein expression is not quantified.","Yes","Yes"]
["Mammals","Uterotrophic assay",1,"Lee et al. 2015","Conducted as OECD test no. 440, Exposure from PND18, 4 days","Open literature","Lee et al. 2015",2015,"Rat","Sprague Dawley",5,"F","Not reported","Direct","Subcutaneous","500, 1000",500,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",1000,"Organ Weight","Liver weight",{"$f":"IF(Z13<>0,VLOOKUP(Z13,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Increased relative liver weight compared to control, statistically significant but slight increase around 10%.","Relative to bw","Increase",500,1000,"mg/kg bw/day",{"$f":"IF(Z13<>0,VLOOKUP(Z13,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Uterotrophic assay",1,"Lee et al. 2015","Conducted as OECD test no. 440, Exposure from PND18, 4 days","Open literature","Lee et al. 2015",2015,"Rat","Sprague Dawley",5,"F","Not reported","Direct","Subcutaneous","500, 1000",500,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",500,"Clinical chemistry/hormones","Phase I enzyme induction (in vivo)",{"$f":"IF(Z14<>0,VLOOKUP(Z14,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Increased CYP2B1 gene expression in liver (10-fold (500 mg), 30-fold (1000mg) compared to control)","Relative to 18S expression","Increase",null,500,"mg/kg bw/day",{"$f":"IF(Z14<>0,VLOOKUP(Z14,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, T, S"},"Pre-incubation with ERα inhibitor ICI did not affect the results.","Yes","Yes"]
["Mammals","Uterotrophic assay",1,"Lee et al. 2015","Conducted as OECD test no. 440, Exposure from PND18, 4 days","Open literature","Lee et al. 2015",2015,"Rat","Sprague Dawley",5,"F","Not reported","Direct","Subcutaneous","500, 1000",500,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",null,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z15<>0,VLOOKUP(Z15,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"No effect after D4 exposure ","Relative to bw","No effect",1000,null,"mg/kg bw/day",{"$f":"IF(Z15<>0,VLOOKUP(Z15,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"},"E2 treatment induced a 5-fold increase in uterus weight","Yes","Yes"]
["Mammals","Uterotrophic assay",1,"Lee et al. 2015","Exposure from PND18, 4 days","Open literature","Lee et al. 2015",2015,"Rat","Sprague Dawley",5,"F","Not reported","Direct","Subcutaneous","500, 1000",500,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",500,"Clinical chemistry/hormones","[Not in list]",{"$f":"IF(Z16<>0,VLOOKUP(Z16,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Increased (in the uterus) CaBP-9K gene expression (from 500 mg: 1.5-fold, 1000mg: 2.5-fold), no observable effect on protein expression (for all proteins included: assessed from Western blot, not quantified), decreased PR gene expression (1000 mg: 0.6-fold), increased PR protein expression (from 500mg), and decreased Erα gene expression (from 500 mg: 0.5-fold) and had no observable effect on ERα protein expression.","Expression levels relative to stable reference genes or proteins","Change",null,500,"mg/kg bw/day",{"$f":"IF(Z16<>0,VLOOKUP(Z16,Interpretation!$C:$E,3,FALSE),\"\")","v":0},"D4 affected gene and protein expression in a similar manner to EE however with different magnitudes of effect. CaBP-9K mRNA expression was up-regulated about 2- or 3-fold by 500 and 1000 mg/kg of D4, while the regulation by EE was 170-folds higher. PR gene expression was reduced to around 0.6 fold and ERα to around 0.5 fold for both EE and D4. ","Yes","Yes"]
["InVitroEstrogen","ER Binding Assay",2,"Quinn et al. 2007a","In vitro assay","Open literature","Quinn et al. 2007a",2007,"Human","ERα and β binding assay","3 replicates",null,0.99,"[Not in list]","[Not in list]",900,900,900,"ppm",4,"Hours",null,null,900,"Receptor binding","Estrogen receptor",{"$f":"IF(Z17<>0,VLOOKUP(Z17,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 bound Erα, inhibiting estradiol binding with 20%","Absolute","Increase",null,900,"ppm",{"$f":"IF(Z17<>0,VLOOKUP(Z17,Interpretation!$C:$E,3,FALSE),\"\")","v":"E"},"Weak binding of D4 on ERα (ss) (20% inhibition of estradiol binding at 900 ppm (0.45uM), which was the maximal achievable vapor concentration). Diethylstilbestrol applied at 500nM resulted in almost 100% inhibition of estradiol binding.","Yes","Yes"]
["InVitroGeneral","In vitro method (general)",2,"Quinn et al. 2007a","In vitro assay","Open literature","Quinn et al. 2007a",2007,"Human","PRα and β binding assays","3 replicates",null,0.99,"[Not in list]","[Not in list]",900,900,900,"ppm",4,"Hours",null,null,null,"Receptor binding","Progesterone (in vitro)",{"$f":"IF(Z18<>0,VLOOKUP(Z18,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 did not affect PRα and β","Absolute","No effect",900,null,"ppm",{"$f":"IF(Z18<>0,VLOOKUP(Z18,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["InVitroGeneral","In vitro method (general)",2,"Quinn et al. 2007a","In vitro assay","Open literature","Quinn et al. 2007a",2007,"Human","PRβ reporter gene assay in MCF-7 cells","3 replicates",null,0.99,"Uptake from the medium (in vitro)","[Not in list]","0.0001 - 10",1E-4,10,"µM","?","?",null,null,null,"Receptor (trans)activation","Progesterone (in vitro)",{"$f":"IF(Z19<>0,VLOOKUP(Z19,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 did not affect PRα and β reporter gene activity","Relative","No effect",10,null,"µM",{"$f":"IF(Z19<>0,VLOOKUP(Z19,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["InVitroGeneral","In vitro method (general)",2,"Quinn et al. 2007a","In vitro assay","Open literature","Quinn et al. 2007a",2007,"Human","HitHunter (PRα) assay","3 replicates",null,0.99,"Uptake from the medium (in vitro)","[Not in list]","0.0001 - 1",1E-4,1,"Molar","?","?",null,null,null,"Receptor (trans)activation","Progesterone (in vitro)",{"$f":"IF(Z20<>0,VLOOKUP(Z20,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 did not affect PRα in HitHunter assay","Relative","No effect",1,null,"Molar",{"$f":"IF(Z20<>0,VLOOKUP(Z20,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["InVitroEstrogen","Other ER in vitro assay",2,"Quinn et al. 2007a","In vitro assay","Open literature","Quinn et al. 2007a",2007,"Human","Erα reporter gene assay in MCF-7 cells","3 replicates",null,0.99,"Uptake from the medium (in vitro)","[Not in list]","0.0001 - 10",1E-4,10,"µM","?","?",null,null,10,"Receptor (trans)activation","Estrogen receptor",{"$f":"IF(Z21<>0,VLOOKUP(Z21,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 increased ERα reporter gene activation by 5-fold in MCF-7 cells","Relative","Increase",null,10,"µM",{"$f":"IF(Z21<>0,VLOOKUP(Z21,Interpretation!$C:$E,3,FALSE),\"\")","v":"E"},"The ERα reporter gene assay showed a 5-fold induction of reporter gene at 10 µM D4 (highest tested concentration). Estradiol induced 35-fold at 10 nM, BPA 10-fold at 20µM.","Yes","Yes"]
["Mammals","Uterotrophic assay",2,"Quinn et al. 2007a","Ovariectomized adult rats, exposure 16h/day for 3 days","Open literature","Quinn et al. 2007a",2007,"Rat","Sprague Dawley & Fischer 344",10,"F",0.99,"Inhalation","Whole-Body",700,700,700,"ppm",3,"Days","Adult","F",700,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z22<>0,VLOOKUP(Z22,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"D4 increased wet (maximal effect: 2.7-fold in Sprague Dawley rats) and blotted (2.6-fold) uterine weight ","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z22<>0,VLOOKUP(Z22,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"},"Both rat strains showed increased wet and blotted uterine weights after D4 exposure compared to controls. As did weights after exposure to positive controls EE (max 6.5-fold) and genistein (data not shown).","Yes","Yes"]
["Mammals","Uterotrophic assay",2,"Quinn et al. 2007a","Ovariectomized adult rats, exposure 16h/day for 3 days","Open literature","Quinn et al. 2007a",2007,"Rat","Sprague Dawley & Fischer 344",10,"F",0.99,"Inhalation","Whole-Body",700,700,700,"ppm",3,"Days","Adult","F",700,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z23<>0,VLOOKUP(Z23,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"D4 mildly (80% of EE control) suppressed the EE-induced increase in uterine weight in Fischer 344 rats, but not in sprague dawley rats.","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z23<>0,VLOOKUP(Z23,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"},"The highest dose of EE (3 mg/kg/day) was given in combination with D4. D4 mildly (80% of EE control) suppressed the Ethinyl estradiol-induced increase in uterine weight in Fischer 344 rats, indicating a weak anti-estrogenic activity of D4. This effect, however, was not observed in Sprague Dawley rats.","Yes","Yes"]
["Mammals","Uterotrophic assay",2,"Quinn et al. 2007a","Ovariectomized adult rats, exposure 16h/day for 3 days","Open literature","Quinn et al. 2007a",2007,"Rat","Sprague Dawley & Fischer 344",10,"F",0.99,"Inhalation","Whole-Body",700,700,700,"ppm",3,"Days","Adult","F",700,"Organ histopathology","Uterus histopathology (UT assay)",{"$f":"IF(Z24<>0,VLOOKUP(Z24,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"D4 exposure resulted in an increase in both the luminal (maximal increase: 2.6-fold compared to control) and glandular epithelial cell height (maximal increase: 1.6-fold compared to control) in both Sprague dawley and Fischer-344 rats.","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z24<>0,VLOOKUP(Z24,Interpretation!$C:$E,3,FALSE),\"\")","v":"E"},"For comparison highest EE dose increased luminal cell height with maximum 2.8-fold. Addition of D4  to highest EE dose did not alter EE-induced increase in cell heights. D4 thus did not show anti-estrogenic activity on these end points. ","Yes","Yes"]
["Mammals","Hershberger assay",2,"Quinn et al. 2007a","Castrated adult rats, exposure 16h/day for 10 days","Open literature","Quinn et al. 2007a",2007,"Rat","Fischer 344",10,"M",0.99,"Inhalation","Whole-Body",700,700,700,"ppm",10,"Days","Adult","F",null,"Organ Weight","LABC weight (Hershberger)",{"$f":"IF(Z25<>0,VLOOKUP(Z25,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"D4 did not affect ventral prostate (fixed or fresh), seminal vesicles, LABC muscle, glans penis, or Cowper's gland weights, nor affect TP-induced weight increase.","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z25<>0,VLOOKUP(Z25,Interpretation!$C:$E,3,FALSE),\"\")","v":"A"},"D4 did not affect any male reproductive organ weights (ventral prostate (fixed or fresh), seminal vesicles, LABC muscle, glans penis, or Cowper's gland), thus did not show androgenic activity. D4 also did not affect TP-induced reproductive weight increases, thus no anti-androgenic effect of D4 was shown. ","Yes","Yes"]
["InVitroEstrogen","ER Binding Assay",3,"He et al. 2003","In vitro assay","Open literature","He et al. 2003",2003,"Human","ERα and β binding assay","3 replicates",null,"Not reported","[Not in list]","[Not in list]","1.0 × 10−10 - 1.0 × 10−4","1.0 × 10−10 ","1.0 × 10−4 ","Molar",30,"Minutes",null,null,"4.0 × 10−5 ","Receptor binding","Estrogen receptor",{"$f":"IF(Z26<>0,VLOOKUP(Z26,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 decreased E2 binding to ERα (approximately by 25%) but not Erβ indicating a competitive binding of D4 to Erα. ","Absolute","Increase","~1 x 10-6 ","4 x 10-5 ","Molar",{"$f":"IF(Z26<>0,VLOOKUP(Z26,Interpretation!$C:$E,3,FALSE),\"\")","v":"E"}]
["Mammals","Mammals Not il list",3,"He et al. 2003","Exposure for 7 days of 6-7 weeks old mice","Open literature","He et al. 2003",2003,"Mouse","B6C3F1",6,"F","Not reported","Oral","Not specified","1, 10, 50, 100, 250, 500, 1000",1,1000,"mg/kg bw/day",7,"Days","[Not in list]","F",10,"Clinical chemistry/hormones","Estradiol level",{"$f":"IF(Z27<>0,VLOOKUP(Z27,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Serum estradiol was reduced by approximately 50 % by D4 exposure of 1000 mg/kg bw/day. Estradiol levels decreased in a dose-dependent manner from 10 mg/kg bw/day. This was however not statistically assessed. ","Absolute & relative","Decrease",1,"(10) does not seem to have been assessed statistically. ","mg/kg bw/day",{"$f":"IF(Z27<>0,VLOOKUP(Z27,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Dope-dependent reductions in serum E2 levels. Not statistically assessed. ","Yes","Yes"]
["Mammals","Mammals Not il list",3,"He et al. 2003","Exposure for 7 days of 6-7 weeks old mice","Open literature","He et al. 2003",2003,"Mouse","B6C3F1",8,"F","Not reported","Oral","Not specified",1000,1000,1000,"mg/kg bw/day",7,"Days","[Not in list]","F",1000,"Clinical chemistry/hormones","Estradiol level",{"$f":"IF(Z28<>0,VLOOKUP(Z28,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Serum estradiol was reduced in intact, sham-operated and adrenalectomized mice","Absolute","Decrease",null,1000,"mg/kg bw/day",{"$f":"IF(Z28<>0,VLOOKUP(Z28,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",3,"He et al. 2003","Exposure for 7 days of 6-7 weeks old mice","Open literature","He et al. 2003",2003,"Mouse","B6C3F1",8,"F","Not reported","Oral","Not specified",1000,1000,1000,"mg/kg bw/day",7,"Days","[Not in list]","F",1000,"Clinical chemistry/hormones","Other hormones",{"$f":"IF(Z29<>0,VLOOKUP(Z29,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Serum corticosterone increased in D4-exposed intact and sham-operated mice but not in adrenalectomized mice.","Absolute","Increase",null,1000,"mg/kg bw/day",{"$f":"IF(Z29<>0,VLOOKUP(Z29,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},"1000mg/kg  D4 increased serum corticosterone, but not in adrenalectomized mice. It is well known that stress\ninduced activation of the hypothalamic-pituitary-adrenal axis may be associated with a suppression of the hypothalamic-pituitary-gonadal axis - but decreased levels of E2 in the absence of an elevation of corticosteroid in D4-exposed adrenalectomized mice demonstrated that the modulation of E2 by D4 could not be attributed solely to elevated serum corticosteroid levels.","Yes","Yes"]
["Mammals","Uterotrophic assay",3,"He et al. 2003","Exposure for 3 days of 8-9 weeks old ovariectomized mice","Open literature","He et al. 2003",2003,"Mouse","B6C3F1",5,"F","Not reported","Oral","Not specified",1000,1000,1000,"mg/kg bw/day",3,"Days","[Not in list]","F",1000,"Clinical chemistry/hormones","[Not in list]",{"$f":"IF(Z30<>0,VLOOKUP(Z30,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Uterine peroxidase activity was increased by D4 exposure activity (approximately 5-fold compared to control assessed from graph) ","Relative","Increase",null,1000,"mg/kg bw/day",{"$f":"IF(Z30<>0,VLOOKUP(Z30,Interpretation!$C:$E,3,FALSE),\"\")","v":0},"Uterine peroxidase activity increased by D4 exposure in a similar manner to E2 exposure (E2 response was double the D4 response)","Yes","Yes"]
["Mammals","Uterotrophic assay",3,"He et al. 2003","Exposure for 3 days of 8-9 weeks old ovariectomized mice","Open literature","He et al. 2003",2003,"Mouse","B6C3F1",5,"F","Not reported","Oral","Not specified","1, 10, 50, 100, 250, 500, 1000",1,1000,"mg/kg bw/day",3,"Days","[Not in list]","F",250,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z31<>0,VLOOKUP(Z31,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Uterine weight was increased by D4 exposure in a dose-dependent manner from 250 mg/kg (approximately 140%, 150%, and 450% of control at respectively 250, 500, and 1000 mg/kg D4 assessed from graph). Pre-treatment with the ER antagonist ICI 182,780 blocked this effect (assessed at 1000 mg/kg).","Absolute","Increase",100,250,"mg/kg bw/day",{"$f":"IF(Z31<>0,VLOOKUP(Z31,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"},"10 µg/kg E2 increased uterine weight 0.5-fold more than 1000 mg/kg D4. ","Yes","Yes"]
["Mammals","Uterotrophic assay",3,"He et al. 2003","Exposure for 3 days of 8-9 weeks old ovariectomized mice","Open literature","He et al. 2003",2003,"Mouse","ERα KO (129/J/C57BL/6J)",5,"F","Not reported","Oral","Not specified","250, 500, 1000",250,1000,"mg/kg bw/day",3,"Days","[Not in list]","F",null,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z32<>0,VLOOKUP(Z32,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"D4 did not induce an increase in uterus weight in Erα KO mice.  ","Absolute","No effect",1000,null,"mg/kg bw/day",{"$f":"IF(Z32<>0,VLOOKUP(Z32,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"},"D4 increased uterine weights in WT mice but not ERα KO mice. ","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M",700,"In life observation","Body weight",{"$f":"IF(Z33<>0,VLOOKUP(Z33,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Exposure had no effect on body weight or body weight gain with the exception of 700 ppm males in the 24-month exposure group. Mean body weight for this group remained approximately 6% lower than controls for the last few months on study. Statistically significant only for week 97 and at necropsy (month 24)","Absolute","Decrease",150,700,"ppm",{"$f":"IF(Z33<>0,VLOOKUP(Z33,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},"6% weight decrease observed only in males statistically significant at week 97 and necropsy (24 months)","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 23-36 (M, 24 months), 35-45 (F, 24 months) ","M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M + F",150,"Organ Weight","Kidney weight",{"$f":"IF(Z34<>0,VLOOKUP(Z34,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"The 700 ppm exposure increased male and female kidney weight (absolute (5-14%) and relative(6-20%)) after 12 and 24 months. In the 150 ppm exposure group, female but not male rats also showed increased kidney weights at 24 months. ","Absolute and relative","Increase",30,150,"ppm",{"$f":"IF(Z34<>0,VLOOKUP(Z34,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},"An additional recovery group (12 months exposure, 12 months recovery) still showed increased kidney weights in the high dose group. ","No","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 23-36 (M, 24 months), 35-45 (F, 24 months) ","M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M + F",30,"Organ Weight","Liver weight",{"$f":"IF(Z35<>0,VLOOKUP(Z35,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Liver weight increases were evident at 6, 12, and 24-months exposure for both sexes. For males, the liver weight increases were associated with exposure to ≥ 30 ppm D4 at 6 months, ≥150 ppm at 12 months, and 700 ppm D4 at 24-months. Female liver weight increases were statistically significant at all three time points (6, 12, and 24 months) at 700 ppm and at 12 and 24 months with exposure to 150 ppm D4. ","Absolute and relative","Increase",10,30,"ppm",{"$f":"IF(Z35<>0,VLOOKUP(Z35,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 35-45 (24 months) ","F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","F",700,"Organ Weight","Uterus weight (with cervix)",{"$f":"IF(Z36<>0,VLOOKUP(Z36,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Uterine weight (absolute and relative) was increased (24%) in the 700 ppm exposure group at 24 months. ","Absolute and relative","Increase",150,700,"ppm",{"$f":"IF(Z36<>0,VLOOKUP(Z36,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"An additional recovery group (12 months exposure, 12 months recovery) still showed increased relative uterine weight in the high dose group. ","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 23-36 (24 months)","M",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M",700,"Organ Weight","Testis weight",{"$f":"IF(Z37<>0,VLOOKUP(Z37,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Testes weight increase was observed at 12- (8.6% absolute, 8.5% relative to body weight)  and 24-month (21% absolute, 28% relative to body weight) exposure periods for males exposed to 700 ppm D4. After a 12 month recovery period increased absolute (67%), relative to body (67.5%) and brain (66.5%) weight, testis weights were still observed in the 700ppm group.  ","Absolute and Relative","Increase",150,700,"ppm",{"$f":"IF(Z37<>0,VLOOKUP(Z37,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"An additional recovery group (12 months exposure, 12 months recovery) showed increased absolute and relative testis weight in the high dose group. ","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 60 (24 months)","M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M + F",700,"Organ histopathology","Liver histopathology",{"$f":"IF(Z38<>0,VLOOKUP(Z38,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"increased incidence of centrilobular hypertrophy in males and a reduction in basophilic foci in females at 700 ppm at 12 and 24 months.","Absolute","Increase",150,700,"ppm",{"$f":"IF(Z38<>0,VLOOKUP(Z38,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,null,"Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 60 (24 months)","M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","F",30,"Organ histopathology","Kidney histopathology",{"$f":"IF(Z39<>0,VLOOKUP(Z39,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"The incidence of chronic nephropathy was elevated at 24 months for females at≥ 30 ppm.","Absolute","Increase",10,30,"ppm",{"$f":"IF(Z39<>0,VLOOKUP(Z39,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},"Although not statistically significant, the severity scores were generally increasing with increasing exposure concentration for both males and females at 24 months.",null,"Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344","10 (12 months), 60 (24 months)","M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M",30,"Organ histopathology","Spleen histopathology",{"$f":"IF(Z40<>0,VLOOKUP(Z40,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"increased incidence of hematopoietic proliferation in\nthe spleen of 700 ppm females and 30 ppm males at 24 months","Absolute","Increase",10,30,"ppm",{"$f":"IF(Z40<>0,VLOOKUP(Z40,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,null,"Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","F",700,"Organ histopathology","Cervix histopathology",{"$f":"IF(Z41<>0,VLOOKUP(Z41,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"cervical squamous epithelial hyperplasia was observed in 5% (3/60) of high dose females at 24 months (compared to 0% in controls).","Absolute","Increase",150,700,"ppm",{"$f":"IF(Z41<>0,VLOOKUP(Z41,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"These low incidence findings were not considered toxicologically significant by the authors","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","F",700,"Organ histopathology","Ovary histopathology",{"$f":"IF(Z42<>0,VLOOKUP(Z42,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"ovarian atrophy presented in 6.7% (4/60) of high dosed females at 24 months (compared to 1.7% in controls). ","Absolute","Increase",150,700,"ppm",{"$f":"IF(Z42<>0,VLOOKUP(Z42,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"These low incidence findings were not considered toxicologically significant by the authors","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","F",700,"Organ histopathology","Uterus histopathology (with cervix)",{"$f":"IF(Z43<>0,VLOOKUP(Z43,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"An increased incidence of uterine cystic endometrial hyperplasia (from 19 % in controls to 50 % in treated females) was found in females exposed to 700 ppm D4. ","Absolute","Increase",150,700,"ppm",{"$f":"IF(Z43<>0,VLOOKUP(Z43,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"The severity of the changes in uterus and ovaries were increased by increasing exposure, but no information on statistical significance of this is given. ","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"M",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M",150,"Organ histopathology","Testis histopathology",{"$f":"IF(Z44<>0,VLOOKUP(Z44,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Increased incidence of interstitial cell hyperplasia at 24 months of 21.7% (13/60) after exposure to 150 ppm D4, and 26.7% (16/60) after exposure to 700 ppm D4. Controls showed an incidence of 11.7%. ","Absolute","Increase",30,150,"ppm",{"$f":"IF(Z44<>0,VLOOKUP(Z44,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Mean severity score was increasing with increasing dose - not assessed statistically. ","Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"M",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M",null,"Organ histopathology","Testis histopathology",{"$f":"IF(Z45<>0,VLOOKUP(Z45,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect of D4 on testis interstitial cell adenoma","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z45<>0,VLOOKUP(Z45,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","F",null,"Organ histopathology","Uterus histopathology (with cervix)",{"$f":"IF(Z46<>0,VLOOKUP(Z46,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No statistically  significant effect of D4 on incidence of uterine neoplasia but an increased incidence of endometrial adenoma was observed (4/60 in 700 ppm group vs 0/60 in the controls). ","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z46<>0,VLOOKUP(Z46,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Combined chronic toxicity/carcinogenicity studies",4,"Jean and Plotzke et al. 2017","exposure 5 days/week. 7-8 weeks old at exposure initiation","Open literature","Jean and Plotzke et al. 2017",2017,"Rat","Fischer 344",60,"M + F",">99.5%","Inhalation","Whole-Body","10, 30, 150, 700",10,700,"ppm",24,"Months","Adult","M + F",null,"Organ histopathology","Thyroid histopathology",{"$f":"IF(Z47<>0,VLOOKUP(Z47,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No statistically significant effects on the incidence of thyroid gland c-cell neoplasia.","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z47<>0,VLOOKUP(Z47,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",null,"In life observation","Body weight",{"$f":"IF(Z48<>0,VLOOKUP(Z48,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No treatment related effect in body weight","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z48<>0,VLOOKUP(Z48,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ Weight","Kidney weight",{"$f":"IF(Z49<>0,VLOOKUP(Z49,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Absolute (10%) and relative to bw (8%) increase in kidney weight",null,"Increase",null,700,"ppm",{"$f":"IF(Z49<>0,VLOOKUP(Z49,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ Weight","Liver weight",{"$f":"IF(Z50<>0,VLOOKUP(Z50,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Absolute (35%) and relative to bw (33%) increase in liver weight",null,"Increase",null,700,"ppm",{"$f":"IF(Z50<>0,VLOOKUP(Z50,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ Weight","Uterus weight (with cervix)",{"$f":"IF(Z51<>0,VLOOKUP(Z51,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z51<>0,VLOOKUP(Z51,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Also, no weight chances in pituitary, brain, spleen, heart, lungs, and thymus","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ Weight","Ovary weight",{"$f":"IF(Z52<>0,VLOOKUP(Z52,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z52<>0,VLOOKUP(Z52,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Also, no weight chances in pituitary, brain, spleen, heart, lungs, and thymus","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ Weight","Adrenals weight",{"$f":"IF(Z53<>0,VLOOKUP(Z53,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z53<>0,VLOOKUP(Z53,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},"Also, no weight chances in pituitary, brain, spleen, heart, lungs, and thymus","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Reproductive","Estrus cyclicity",{"$f":"IF(Z54<>0,VLOOKUP(Z54,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Increased cumulative number of days (6966) in estrogen-predominant days (proestrous and estrous) in the estrous cycle in D4 group compared to controls (4152). Percent also increased. ","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z54<>0,VLOOKUP(Z54,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Reproductive","Estrus cyclicity",{"$f":"IF(Z55<>0,VLOOKUP(Z55,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Increased mean estrous cycle incidence compared to control","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z55<>0,VLOOKUP(Z55,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Reproductive","Estrus cyclicity",{"$f":"IF(Z56<>0,VLOOKUP(Z56,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Increased duration of proestrous/estrous phases (2.4-3.5 days/cycle compared to control with 1-2 days/cycle)","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z56<>0,VLOOKUP(Z56,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Only statistically significant in interval 1-6 out of 9, each interval was 45 days. ","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Clinical chemistry/hormones","Progesterone",{"$f":"IF(Z57<>0,VLOOKUP(Z57,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Increased serum progesterone from week 2-10 out of 57 weeks (approximately 40% increased compared to control, assessed from graph)","Absolute per liter serum","Increase",null,700,"ppm",{"$f":"IF(Z57<>0,VLOOKUP(Z57,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Clinical chemistry/hormones","Estradiol level",{"$f":"IF(Z58<>0,VLOOKUP(Z58,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Decreased serum estradiol over the entire study period (maximally around 167% increased compared to control, assessed from graph) ","Absolute per liter serum","Decrease",null,700,"ppm",{"$f":"IF(Z58<>0,VLOOKUP(Z58,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Clinical chemistry/hormones","[Not in list]",{"$f":"IF(Z59<>0,VLOOKUP(Z59,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Decreased (10-30%) corticosterone levels were observed from weeks 2-51 out of 57 weeks. ","Absolute per liter serum","Decrease",null,700,"ppm",{"$f":"IF(Z59<>0,VLOOKUP(Z59,Interpretation!$C:$E,3,FALSE),\"\")","v":0},null,"Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ histopathology","Uterus histopathology (with cervix)",{"$f":"IF(Z60<>0,VLOOKUP(Z60,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"An increased incidence of cystic endometrial hyperplasia was observed (14/37 compared to control with 8/37)","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z60<>0,VLOOKUP(Z60,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Results were not subjected to statistical analysis","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ histopathology","Ovary histopathology",{"$f":"IF(Z61<>0,VLOOKUP(Z61,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Decrease (37%) in the incidence of antral-size atretic follicles in the ovaries","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z61<>0,VLOOKUP(Z61,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Results were not subjected to statistical analysis","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ histopathology","Vagina histopathology",{"$f":"IF(Z62<>0,VLOOKUP(Z62,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Increase in severity was observed for epithelial thickness compared to controls","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z62<>0,VLOOKUP(Z62,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Results were not subjected to statistical analysis","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Organ histopathology","Vagina histopathology",{"$f":"IF(Z63<>0,VLOOKUP(Z63,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"D4-exposed animals also had a slightly lower incidence of vaginal mucification than controls – but for those animals in the D4-group that did display mucification there was a shift to moderate and severe severity.",null,"Change",null,700,"ppm",{"$f":"IF(Z63<>0,VLOOKUP(Z63,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Results were not subjected to statistical analysis","Yes","Yes"]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",700,"Clinical chemistry/hormones","Follicle Stimulating Hormone (FSH) level",{"$f":"IF(Z64<>0,VLOOKUP(Z64,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"12% lower serum FSH levels at necropsy but no statistical significance","Absolute per liter serum","No effect",700,null,"ppm",{"$f":"IF(Z64<>0,VLOOKUP(Z64,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",700,"In life observation","Body weight",{"$f":"IF(Z65<>0,VLOOKUP(Z65,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Lower mean body weight gain during gestation (86% of control)","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z65<>0,VLOOKUP(Z65,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",700,"Organ Weight","[Not in list]",{"$f":"IF(Z66<>0,VLOOKUP(Z66,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Gravid uterine weight decreased after 700 ppm D4 exposure","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z66<>0,VLOOKUP(Z66,Interpretation!$C:$E,3,FALSE),\"\")","v":0},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"In life observation","Clinical signs",{"$f":"IF(Z67<>0,VLOOKUP(Z67,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No treatment related clinical signs were observed","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z67<>0,VLOOKUP(Z67,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",700,"Organ Weight","Adrenals weight",{"$f":"IF(Z68<>0,VLOOKUP(Z68,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Mean absolute maternal adrenal gland weight was increased in high dose group (16.8% compared to control)","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z68<>0,VLOOKUP(Z68,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"Organ Weight","Brain weight",{"$f":"IF(Z69<>0,VLOOKUP(Z69,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z69<>0,VLOOKUP(Z69,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,null,"Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"Organ Weight","Ovary weight",{"$f":"IF(Z70<>0,VLOOKUP(Z70,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z70<>0,VLOOKUP(Z70,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"Organ Weight","Thyroid weight",{"$f":"IF(Z71<>0,VLOOKUP(Z71,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z71<>0,VLOOKUP(Z71,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"Reproductive","Time to mating",{"$f":"IF(Z72<>0,VLOOKUP(Z72,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z72<>0,VLOOKUP(Z72,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"Reproductive","Fertility (mammals)",{"$f":"IF(Z73<>0,VLOOKUP(Z73,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect of D4 on fertility indices compared to control","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z73<>0,VLOOKUP(Z73,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",300,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z74<>0,VLOOKUP(Z74,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Decreased number of corpora lutea in 300 (90% of control) and 500 (87% of control) ppm groups. Decreased number of implantation sites in 500 (79% of control) and 700 (68% of control) ppm groups","Absolute","Decrease",70,300,"ppm",{"$f":"IF(Z74<>0,VLOOKUP(Z74,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",700,"Reproductive","Pre implantation loss",{"$f":"IF(Z75<>0,VLOOKUP(Z75,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Increased % pre-implantation loss in 700 ppm group","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z75<>0,VLOOKUP(Z75,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",null,"Reproductive","Post implantation loss",{"$f":"IF(Z76<>0,VLOOKUP(Z76,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No statistically significant effect on % post-implantation loss in D4 groups, but absolute number increased with exposure from 500 ppm D4 (control 7.8%, 30 ppm D4 6.1%, 300ppm D4 7.5, 500 ppm D4 11.3%, 700 ppm D4 16.6%)","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z76<>0,VLOOKUP(Z76,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 28 days prior to mating to GD19. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","21-23","F",">99%","Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm",37,"Days","Adult","F",500,"Reproductive","Litter viability",{"$f":"IF(Z77<>0,VLOOKUP(Z77,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Number of viable fetuses was decreased in 500 and 700 ppm groups","Absolute","Decrease",300,500,"ppm",{"$f":"IF(Z77<>0,VLOOKUP(Z77,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"},null,"Yes","Yes"]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"In life observation","Clinical signs",{"$f":"IF(Z78<>0,VLOOKUP(Z78,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No exposure-related clinical signs were observed","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z78<>0,VLOOKUP(Z78,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"In life observation","Body weight",{"$f":"IF(Z79<>0,VLOOKUP(Z79,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No effect on maternal body weight gain during gestation","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z79<>0,VLOOKUP(Z79,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Organ Weight","Brain weight",{"$f":"IF(Z80<>0,VLOOKUP(Z80,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z80<>0,VLOOKUP(Z80,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Organ Weight","Ovary weight",{"$f":"IF(Z81<>0,VLOOKUP(Z81,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z81<>0,VLOOKUP(Z81,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Organ Weight","Adrenals weight",{"$f":"IF(Z82<>0,VLOOKUP(Z82,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z82<>0,VLOOKUP(Z82,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Organ Weight","Thyroid weight",{"$f":"IF(Z83<>0,VLOOKUP(Z83,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z83<>0,VLOOKUP(Z83,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Reproductive","Time to mating",{"$f":"IF(Z84<>0,VLOOKUP(Z84,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z84<>0,VLOOKUP(Z84,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z85<>0,VLOOKUP(Z85,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z85<>0,VLOOKUP(Z85,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Organ Weight","[Not in list]",{"$f":"IF(Z86<>0,VLOOKUP(Z86,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"No effect on gravid uterine weight","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z86<>0,VLOOKUP(Z86,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Reproductive","Pre implantation loss",{"$f":"IF(Z87<>0,VLOOKUP(Z87,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z87<>0,VLOOKUP(Z87,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Reproductive","Post implantation loss",{"$f":"IF(Z88<>0,VLOOKUP(Z88,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z88<>0,VLOOKUP(Z88,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 31 days prior to mating to 3 days prior to mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","26 control, 50 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",28,"Days","Adult","F",null,"Reproductive","Litter viability",{"$f":"IF(Z89<>0,VLOOKUP(Z89,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z89<>0,VLOOKUP(Z89,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",null,"In life observation","Clinical signs",{"$f":"IF(Z90<>0,VLOOKUP(Z90,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No exposure-related clinical signs were observed","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z90<>0,VLOOKUP(Z90,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"In life observation","Body weight",{"$f":"IF(Z91<>0,VLOOKUP(Z91,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Lower mean body weight gain during gestation (87% of control)","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z91<>0,VLOOKUP(Z91,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"Organ Weight","Ovary weight",{"$f":"IF(Z92<>0,VLOOKUP(Z92,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Mean absolute maternal ovary weight was decreased in the 700 ppm group by 10.1% compared to control","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z92<>0,VLOOKUP(Z92,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",null,"Organ Weight","Adrenals weight",{"$f":"IF(Z93<>0,VLOOKUP(Z93,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z93<>0,VLOOKUP(Z93,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",null,"Organ Weight","Brain weight",{"$f":"IF(Z94<>0,VLOOKUP(Z94,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z94<>0,VLOOKUP(Z94,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",null,"Organ Weight","Thyroid weight",{"$f":"IF(Z95<>0,VLOOKUP(Z95,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z95<>0,VLOOKUP(Z95,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"Organ Weight","[Not in list]",{"$f":"IF(Z96<>0,VLOOKUP(Z96,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Gravid uterine weight decreased after 700 ppm D4 exposure","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z96<>0,VLOOKUP(Z96,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z97<>0,VLOOKUP(Z97,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Number of corpora lutea decreased in D4 group (85% of control). Number of implantation sites decreased (69% of control)","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z97<>0,VLOOKUP(Z97,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"Reproductive","Pre implantation loss",{"$f":"IF(Z98<>0,VLOOKUP(Z98,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Increased in D4 group (28.4%) compared to control (9.8%).","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z98<>0,VLOOKUP(Z98,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"Reproductive","Post implantation loss",{"$f":"IF(Z99<>0,VLOOKUP(Z99,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Increased post-implantation loss in D4 group (18%) compared to control (6.4%). ","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z99<>0,VLOOKUP(Z99,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days prior to mating to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","28 control, 19 exposed","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",6,"Days","Adult","F",700,"Reproductive","Litter viability",{"$f":"IF(Z100<>0,VLOOKUP(Z100,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Decreased number of viable fetuses in D4 group (61% of control).","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z100<>0,VLOOKUP(Z100,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"In life observation","Clinical signs",{"$f":"IF(Z101<>0,VLOOKUP(Z101,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Observed in both control group and D4 exposed group","Absolute","Change",null,null,"ppm",{"$f":"IF(Z101<>0,VLOOKUP(Z101,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Organ Weight","Adrenals weight",{"$f":"IF(Z102<>0,VLOOKUP(Z102,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z102<>0,VLOOKUP(Z102,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Organ Weight","Brain weight",{"$f":"IF(Z103<>0,VLOOKUP(Z103,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z103<>0,VLOOKUP(Z103,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Organ Weight","Ovary weight",{"$f":"IF(Z104<>0,VLOOKUP(Z104,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z104<>0,VLOOKUP(Z104,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Organ Weight","Thyroid weight",{"$f":"IF(Z105<>0,VLOOKUP(Z105,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z105<>0,VLOOKUP(Z105,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z106<>0,VLOOKUP(Z106,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z106<>0,VLOOKUP(Z106,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Reproductive","Litter viability",{"$f":"IF(Z107<>0,VLOOKUP(Z107,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z107<>0,VLOOKUP(Z107,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Reproductive","Post implantation loss",{"$f":"IF(Z108<>0,VLOOKUP(Z108,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z108<>0,VLOOKUP(Z108,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Reproductive","Pre implantation loss",{"$f":"IF(Z109<>0,VLOOKUP(Z109,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z109<>0,VLOOKUP(Z109,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD2-5. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley",23,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",4,"Days","Adult","F",null,"Organ Weight","[Not in list]",{"$f":"IF(Z110<>0,VLOOKUP(Z110,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"No effect on gravid uterine weight","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z110<>0,VLOOKUP(Z110,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day on either 4, 3, 2, or 1 day pre-mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","11-40","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",1,"Day","Adult","F",700,"Reproductive","Fertility (mammals)",{"$f":"IF(Z111<>0,VLOOKUP(Z111,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Fertility index decreased after D4 exposure 1 day before mating (64.7%) compared to control (95.5%). ","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z111<>0,VLOOKUP(Z111,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day on either 4, 3, 2, or 1 day pre-mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","11-40","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",1,"Day","Adult","F",null,"Organ Weight","[Not in list]",{"$f":"IF(Z112<>0,VLOOKUP(Z112,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"No effect on gravid uterine weight","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z112<>0,VLOOKUP(Z112,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day on either 4, 3, 2, or 1 day pre-mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","11-40","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",1,"Day","Adult","F",null,"In life observation","Body weight",{"$f":"IF(Z113<>0,VLOOKUP(Z113,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No effect on maternal GD0-8 body weight gain","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z113<>0,VLOOKUP(Z113,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day on either 4, 3, 2, or 1 day pre-mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","11-40","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",1,"Day","Adult","F",null,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z114<>0,VLOOKUP(Z114,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect of exposure on corpora lutea or number of implantation sites","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z114<>0,VLOOKUP(Z114,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day on either 4, 3, 2, or 1 day pre-mating. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","11-40","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",1,"Day","Adult","F",null,"Reproductive","Pre implantation loss",{"$f":"IF(Z115<>0,VLOOKUP(Z115,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect on % pre-implantation loss","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z115<>0,VLOOKUP(Z115,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days before mating to GD1 or to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","36-39","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","4-6","Days","Adult","F",700,"In life observation","Body weight",{"$f":"IF(Z116<>0,VLOOKUP(Z116,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Increased maternal GD0-8 body weight gain (128% of control) in the 'day -3 to GD1' exposure group.","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z116<>0,VLOOKUP(Z116,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days before mating to GD1 or to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","36-39","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","4-6","Days","Adult","F",null,"Reproductive","Fertility (mammals)",{"$f":"IF(Z117<>0,VLOOKUP(Z117,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect on fertility index (%)","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z117<>0,VLOOKUP(Z117,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days before mating to GD1 or to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","36-39","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","4-6","Days","Adult","F",700,"Organ Weight","[Not in list]",{"$f":"IF(Z118<>0,VLOOKUP(Z118,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Decreased gravid uterine weight in 'day -3 to GD3' exposure group","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z118<>0,VLOOKUP(Z118,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days before mating to GD1 or to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","36-39","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","4-6","Days","Adult","F",700,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z119<>0,VLOOKUP(Z119,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Decreased number of corpora lutea in 'day -3 to GD3' exposure group (87% of control). No statistically significant effect on number of implantation sites. ","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z119<>0,VLOOKUP(Z119,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from 3 days before mating to GD1 or to GD3. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","36-39","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","4-6","Days","Adult","F",null,"Reproductive","Pre implantation loss",{"$f":"IF(Z120<>0,VLOOKUP(Z120,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect on % pre-implantation loss","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z120<>0,VLOOKUP(Z120,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD0 to GD2. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","22-24","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","1-3","Days","Adult","F",null,"Reproductive","Fertility (mammals)",{"$f":"IF(Z121<>0,VLOOKUP(Z121,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect of short post-mating exposure on fertility index (%)","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z121<>0,VLOOKUP(Z121,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD0 to GD2. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","22-24","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","1-3","Days","Adult","F",null,"Organ Weight","[Not in list]",{"$f":"IF(Z122<>0,VLOOKUP(Z122,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"No effect of short post-mating exposure on gravid uterine weight","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z122<>0,VLOOKUP(Z122,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD0 to GD2. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","22-24","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","1-3","Days","Adult","F",null,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z123<>0,VLOOKUP(Z123,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect of short post-mating exposure on number of corpora lutea or number of implantation sites ","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z123<>0,VLOOKUP(Z123,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",6,"Meeks et al. 2007","Exposure 6 hours/day from GD0 to GD2. 73-85 days old at initiation of exposure.","Open literature","Meeks et al. 2007",2007,"Rat","Sprague-Dawley","22-24","F",">99%","Inhalation","Whole-Body",700,700,700,"ppm","1-3","Days","Adult","F",null,"Reproductive","Pre implantation loss",{"$f":"IF(Z124<>0,VLOOKUP(Z124,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect of short post-mating exposure on % pre-implantation loss ","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z124<>0,VLOOKUP(Z124,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",700,"In life observation","Body weight",{"$f":"IF(Z125<>0,VLOOKUP(Z125,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Reductions in mean terminal body weight occurred in both treatment groups, relative to controls (252±2.7 and 255±2.1 g, respectively, versus 263±2.5 g, so only 3-4%.","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z125<>0,VLOOKUP(Z125,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",null,"Organ Weight","Brain weight",{"$f":"IF(Z126<>0,VLOOKUP(Z126,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute and relative","No effect",900,null,"ppm",{"$f":"IF(Z126<>0,VLOOKUP(Z126,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",null,"Organ Weight","Ovary weight",{"$f":"IF(Z127<>0,VLOOKUP(Z127,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",900,null,"ppm",{"$f":"IF(Z127<>0,VLOOKUP(Z127,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",null,"Organ Weight","Uterus weight (with cervix)",{"$f":"IF(Z128<>0,VLOOKUP(Z128,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute and relative","No effect",900,null,"ppm",{"$f":"IF(Z128<>0,VLOOKUP(Z128,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",900,"In life observation","Body weight",{"$f":"IF(Z129<>0,VLOOKUP(Z129,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Reduction in mean terminal body weight was observed only at 900 ppm\n(260±3.0 g versus 270±2.2 g in control, so only 4%)","Absolute","Decrease",700,900,"ppm",{"$f":"IF(Z129<>0,VLOOKUP(Z129,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",900,"Organ Weight","Ovary weight",{"$f":"IF(Z130<>0,VLOOKUP(Z130,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Decreased ovarian weight was observed in the 900 ppm group, both absolute and relative to body weight and brain weight","Absolute and relative","Decrease",700,900,"ppm",{"$f":"IF(Z130<>0,VLOOKUP(Z130,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"The effects remained in ovulating rats after grouping of the animals according to ovulatory status (ovulators vs non-ovulators). Decreased ovarian weights, both absolute and relative to brain weight, were observed in the 900 ppm group."]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",900,"Organ Weight","Uterus weight (with cervix)",{"$f":"IF(Z131<>0,VLOOKUP(Z131,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Decreased uterus/body weight in 900 ppm group compared to control","Relative","Decrease",700,900,"ppm",{"$f":"IF(Z131<>0,VLOOKUP(Z131,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",700,"Clinical chemistry/hormones","Estradiol level",{"$f":"IF(Z132<>0,VLOOKUP(Z132,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Increases in plasma estrone levels but not estradiol or estrone/estradiol ratios were observed at 700 and 900 ppm","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z132<>0,VLOOKUP(Z132,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",900,"Clinical chemistry/hormones","Progesterone",{"$f":"IF(Z133<>0,VLOOKUP(Z133,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Increased plasma progesterone levels in 900 ppm group","Absolute","Increase",700,900,"ppm",{"$f":"IF(Z133<>0,VLOOKUP(Z133,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 2 days from their third diestrus day and for 2.5 hours during proestrous. 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","22-27","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",2.1,"Days","Adult","F",null,"Clinical chemistry/hormones","Follicle Stimulating Hormone (FSH) level",{"$f":"IF(Z134<>0,VLOOKUP(Z134,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"No effect","Absolute","No effect",900,null,"ppm",{"$f":"IF(Z134<>0,VLOOKUP(Z134,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",700,"Clinical chemistry/hormones","Luteinizing Hormone (LH) level",{"$f":"IF(Z135<>0,VLOOKUP(Z135,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Plasma LH levels were lower than controls at the 4, 6, and 8 p.m. time points\nin the 700 ppm exposure group, achieving a significant reduction\nonly at the 6 p.m. time point (7.9±1.7 ng/mL compared with\n14.2±2.2 ng/mL in the controls) (Fig. 4). Significantly lower\nLH levels were observed at the 4, 6, and 8 p.m. measurements\nin the 900 ppm exposure group (Fig. 4). The area under the LH\ncurve was also significantly less in the 900 ppm group, but not\nin the 700 ppm group, relative to controls. When grouped by ovulatory status, ovulating or non-ovulating rats, there were no treatment-related differences in\nthe mean plasma LH levels. Every animal that failed to produce an LH surge failed to ovulate.","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z135<>0,VLOOKUP(Z135,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Some individual Phase II (3 day exposure) control rats lacked an LH peak entirely or had the highest LH value occurring before or after 6 p.m. Conversely, the LH peak in a few D4-treated animals was not affected, while some animals exhibited early or delayed suppression of the LH peak."]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",700,"Reproductive","[Not in list]",{"$f":"IF(Z136<>0,VLOOKUP(Z136,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Exposure to D4 at 700 and 900 ppm significantly decreased the proportion of rats\nthat ovulated (79% of controls, 42% of 700 ppm, and 31% of 900 ppm exposed rats).","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z136<>0,VLOOKUP(Z136,Interpretation!$C:$E,3,FALSE),\"\")","v":0},"Analysis of the peak-centered LH profile by ovulatory status, demonstrated that ovulating\nrats exposed to D4 could not be distinguished from ovulating controls; similarly, those that failed to ovulate also could not be distinguished from non-ovulating controls."]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",700,"Clinical chemistry/hormones","Prolactin",{"$f":"IF(Z137<>0,VLOOKUP(Z137,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Reduction in PRL levels was noted only at the\n2 p.m. time point in both exposure groups (time points: 2, 4, 6, 8, 10 p.m.)","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z137<>0,VLOOKUP(Z137,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, T, S"},"The area under the PRL curves for 700 ppm (987±121) and 900 ppm (1094±144) D4 exposure groups were not statistically significantly\ndifferent from the control group (644±109). When the animals were grouped by ovulatory status, a significant reduction in PRL levels was observed only in the ovulating females in the 900 ppm exposure group at 2 p.m. only (118.4±35.7 ng/mL\nversus 195.2±28.1 ng/mL in controls."]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",700,"Clinical chemistry/hormones","Estradiol level",{"$f":"IF(Z138<>0,VLOOKUP(Z138,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Mean plasma E2 levels on the morning of estrous were elevated\nin the 700 and 900 ppm exposure groups (22.2±4.3 and\n21.2±1.8 pg/mL, respectively) compared to the control group\n(7.76±1.4 pg/mL). Plasma E1 levels in D4-treated rats were significantly\nhigher in both the 700 (72.0±3.4 pg/mL) and 900 ppm\n(79.1±4.4 pg/mL) exposure groups relative to controls\n(51.5±3.1 pg/mL). Statistically significant\nreductions in E1/E2 ratios were observed both in the 700\nand 900 ppm exposure groups relative to the plasma E1/E2\nratios in control rats.","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z138<>0,VLOOKUP(Z138,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"This increase in E2 continued to be significant in both ovulating and non-ovulating rats compared to the controls (Fig. 9). However, the treatment-related increase in estrus day E2 was larger in non-ovulating rats. There were no significant differences in E1/E2 ratios among ovulating rats. Plasma E1/E2 ratios among non-ovulating rats were significantly decreased in the 900 ppm exposure group (3.8±0.4) relative to controls (7.9±1.7). "]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",700,"Clinical chemistry/hormones","Follicle Stimulating Hormone (FSH) level",{"$f":"IF(Z139<>0,VLOOKUP(Z139,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Mean plasma FSH levels on the morning of estrous were decreased after both 700 and 900 ppm D4 exposure","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z139<>0,VLOOKUP(Z139,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",null,"Clinical chemistry/hormones","Progesterone",{"$f":"IF(Z140<>0,VLOOKUP(Z140,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"No effects on progesterone levels on the morning of estrous","Absolute","No effect",900,null,"ppm",{"$f":"IF(Z140<>0,VLOOKUP(Z140,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",700,"Organ histopathology","Oviduct histopathology",{"$f":"IF(Z141<>0,VLOOKUP(Z141,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Reduction in the mean number of ova in the oviducts on the day of estrus in\nboth exposure groups (4.8±0.97 and 2.8±0.71 ova/rat) relative to controls (8.7±0.78 ova/rat","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z141<>0,VLOOKUP(Z141,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"Significant decreases in the mean number of ova/rat were also observed when the data were analyzed by the left or right oviduct. When analyzed by ovulatory status, the mean number of ova in ovulating D4-exposed rats at 700 or 900 ppm (12.1±0.84, and 9.5±0.9 ova/rat, respectively) were not statistically different from the mean number of ova in the control group (11.1±0.56 ova/rat)."]
["Mammals","Mammals Not il list",7,"Quinn et al. 2007b","Exposure 6 hours/day for 3 days from the third day of diestrus (2 days) and through proestrous (1 day). 13 weeks of age at initiation of exposure.","Open literature","Quinn et al. 2007b",2007,"Rat","Sprague-Dawley","10-36","F",0.996,"Inhalation","Whole-Body","700, 900",700,900,"ppm",3,"Days","Adult","F",null,"Organ histopathology","Ovary histopathology",{"$f":"IF(Z142<>0,VLOOKUP(Z142,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No change in the number of Corpora lutea was detectable among ovulating rats","Absolute","No effect",900,null,"ppm",{"$f":"IF(Z142<>0,VLOOKUP(Z142,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"},"There was an inconsistent weak trend toward increased numbers of persistent mature follicles (>500  m) in exposed rats statistically identified in 700 ppm ovulators and 900 ppm nonovulators), which correlated with elevated estradiol levels on\nthe morning of estrus in treated animals that ovulated. However, because large ovarian structures were often counted in more than one section, and structures on the unsampled parts of the ovary were not counted, the data obtained should not be interpreted as the actual number. The numbers are valid for comparison purposes only."]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley",30,"M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125","Days","Adult (F0)","M + F",null,"In life observation","Clinical signs",{"$f":"IF(Z143<>0,VLOOKUP(Z143,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No exposure-related clinical signs were observed","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z143<>0,VLOOKUP(Z143,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"},"Two cases of death due to dystocia of females in the high exposure group. "]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","≥138 days","Days","Adult (F1)","M + F",null,"In life observation","Clinical signs",{"$f":"IF(Z144<>0,VLOOKUP(Z144,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No exposure-related clinical signs were observed","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z144<>0,VLOOKUP(Z144,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","12-29 litters","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","Indirect during gestation and lactation","Days","Offspring (F2)","M + F",null,"In life observation","Clinical signs",{"$f":"IF(Z145<>0,VLOOKUP(Z145,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No exposure-related clinical signs were observed","Absolute","No effect",700,null,null,{"$f":"IF(Z145<>0,VLOOKUP(Z145,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley",30,"M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125","Days","Adult (F0)","M",null,"In life observation","[Not in list]",{"$f":"IF(Z146<>0,VLOOKUP(Z146,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Ejaculatory plug production increased with exposure and was 0.033, 0.023, 0.058, 0.332 and 0.600 plugs/rat/day in the 0, 70, 300, 500 and 700 ppm groups,\nrespectively. No statistical analysis was performed.","Absolute","Change",null,null,"ppm",{"$f":"IF(Z146<>0,VLOOKUP(Z146,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","≥138 days","Days","Adult (F1)","M",null,"In life observation","[Not in list]",{"$f":"IF(Z147<>0,VLOOKUP(Z147,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Ejaculatory plug production increased with exposure and was 0.027, 0.030, 0.052, 0.112 and 0.425 plugs/rat/day in the 0, 70, 300, 500 and 700 ppm groups,\nrespectively. No statistical analysis was performed.","Absolute","Change",null,null,"ppm",{"$f":"IF(Z147<>0,VLOOKUP(Z147,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","≥138 days","Days","Adult (F1)","M + F",null,"In life observation","Body weight",{"$f":"IF(Z148<>0,VLOOKUP(Z148,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Mean weekly body weight were comparable between groups.","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z148<>0,VLOOKUP(Z148,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley",30,"M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125","Days","Adult (F0)","M + F",null,"In life observation","Body weight",{"$f":"IF(Z149<>0,VLOOKUP(Z149,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Mean weekly body weight were comparable between groups.","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z149<>0,VLOOKUP(Z149,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley",30,"M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125","Days","Adult (F0)","M",700,"In life observation","Food consumption",{"$f":"IF(Z150<>0,VLOOKUP(Z150,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Food consumption and mean body weight gain was reduced in week 1 of exposure in 700 ppm males","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z150<>0,VLOOKUP(Z150,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","≥138 days","Days","Adult (F1)","M",700,"In life observation","Food consumption",{"$f":"IF(Z151<>0,VLOOKUP(Z151,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Food consumption and mean body weight gain was reduced in week 1 of exposure in 700 ppm males","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z151<>0,VLOOKUP(Z151,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","≥138 days","Days","Adult (F1)","F",700,"In life observation","Body weight",{"$f":"IF(Z152<>0,VLOOKUP(Z152,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Maternal body weight gain during gestation was reduced in 700 ppm females (104g compared to 126g in control group). This may be the result of the reduced number of pups.","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z152<>0,VLOOKUP(Z152,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",300,"Organ Weight","Liver weight",{"$f":"IF(Z153<>0,VLOOKUP(Z153,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Increased relative liver weight (9-18.5%) in 300, 500, and 700 ppm males, also absolute weight in 700 ppm males (16%). In F0 females, absolute and relative liver weights were increased (9-33%) after 300, 500, and 700 ppm D4 exposure. For F1 females, absolute and relative liver weights were increased (14-33%) after 500 and 700 ppm D4. ","Absolute and relative","Increase",70,300,"ppm",{"$f":"IF(Z153<>0,VLOOKUP(Z153,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",300,"Organ Weight","Kidney weight",{"$f":"IF(Z154<>0,VLOOKUP(Z154,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Relative kidney weights were increased in F0 males from 300 ppm (8%-15%), absolute from 500 ppm (8-11%). For F1 males only relative kidney weights were increased (9-11%) from 500 ppm D4 exposure. In females only 700 ppm D4 in F1 females increased the absolute (13%) and relative (9%) kidney weight.","Absolute and relative","Increase",70,300,"ppm",{"$f":"IF(Z154<>0,VLOOKUP(Z154,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",700,"Organ Weight","Pituitary weight",{"$f":"IF(Z155<>0,VLOOKUP(Z155,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Increased relative pituitary weight in F0 700 ppm males (OBS! the table in the paper reports the same values for control and exposed). Absolute and relative pituitary weight in F1 700 ppm females was increased (33-40%). ","Absolute and relative","Increase",500,700,"ppm",{"$f":"IF(Z155<>0,VLOOKUP(Z155,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M",null,"Organ Weight","Testis weight",{"$f":"IF(Z156<>0,VLOOKUP(Z156,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect on left or right testis weight","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z156<>0,VLOOKUP(Z156,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","F",null,"Organ Weight","Ovary weight",{"$f":"IF(Z157<>0,VLOOKUP(Z157,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect on ovary weight","Absolute and relative","No effect",700,null,"ppm",{"$f":"IF(Z157<>0,VLOOKUP(Z157,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M",700,"Organ histopathology","Kidney histopathology",{"$f":"IF(Z158<>0,VLOOKUP(Z158,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Increased incidence of tubular mineralization in kidneys from 700 ppm exposed F0 and F1 males (data not shown). ","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z158<>0,VLOOKUP(Z158,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",500,"Organ histopathology","Liver histopathology",{"$f":"IF(Z159<>0,VLOOKUP(Z159,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Increased incidence of hepatocyte hypertrophy in F1 females after 500 and 700 ppm D4 and in F1 700 ppm males. ","Absolute","Increase",300,500,"ppm",{"$f":"IF(Z159<>0,VLOOKUP(Z159,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M",700,"Organ histopathology","Liver histopathology",{"$f":"IF(Z160<>0,VLOOKUP(Z160,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"The incidence of pigment in the liver was increased in 700 ppm F1 males. The\npigment was extracellular in periportal regions and morphologically\ncompatible with bile pigment. The incidence of bile duct\nhyperplasia was increased in 700 ppm F1 males","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z160<>0,VLOOKUP(Z160,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",700,"Organ histopathology","Lung histopathology",{"$f":"IF(Z161<>0,VLOOKUP(Z161,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Significant increases in the incidence of focal alveolar histiocytosis were noted in the\nlungs of 700 ppm F0 and F1 females and the F1 males.","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z161<>0,VLOOKUP(Z161,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) ","Days","Adult (F0)","F",null,"Organ histopathology","Ovary histopathology",{"$f":"IF(Z162<>0,VLOOKUP(Z162,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No evidence of exposure-related effects","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z162<>0,VLOOKUP(Z162,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) ","Days","Adult (F0)","F",null,"Organ histopathology","Vagina histopathology",{"$f":"IF(Z163<>0,VLOOKUP(Z163,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No evidence of exposure-related effects","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z163<>0,VLOOKUP(Z163,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) ","Days","Adult (F0)","F",null,"Organ histopathology","Uterus histopathology (with cervix)",{"$f":"IF(Z164<>0,VLOOKUP(Z164,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No evidence of exposure-related effects","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z164<>0,VLOOKUP(Z164,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) ","Days","Adult (F0)","F",null,"Organ histopathology","Mammary gland histopathology (female)",{"$f":"IF(Z165<>0,VLOOKUP(Z165,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No evidence of exposure-related effects","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z165<>0,VLOOKUP(Z165,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) ","Days","Adult (F0)","F",null,"Organ histopathology","Pituitary histopathology",{"$f":"IF(Z166<>0,VLOOKUP(Z166,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No evidence of exposure-related effects","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z166<>0,VLOOKUP(Z166,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) ","Days","Adult (F0)","F",null,"Reproductive","Estrus cyclicity",{"$f":"IF(Z167<>0,VLOOKUP(Z167,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No evidence of exposure-related effects","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z167<>0,VLOOKUP(Z167,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body",700,700,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","F",null,"Reproductive","Number of ovarian follicles",{"$f":"IF(Z168<>0,VLOOKUP(Z168,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No treatment-related differences in ovarian primordial follicle counts or number of sections with growing follicles present. ","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z168<>0,VLOOKUP(Z168,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm"," ≥138 days (F1)","Days","Adult (F1)","F",700,"Reproductive","Estrus cyclicity",{"$f":"IF(Z169<>0,VLOOKUP(Z169,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"15/30 females in the 700 ppm group were anovulatory or had abnormal estrous cycles (5.3 days compared to 4.2 in controls)","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z169<>0,VLOOKUP(Z169,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm"," ≥138 days (F1)","Days","Adult (F1)","F",null,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z170<>0,VLOOKUP(Z170,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Number of rats with corpora lutea of pregnancy\nwas 26/30, 20/30, 21/30, 18/30, and 12/30 rats in the control,\n70, 300, 500, and 700 ppm groups, respectively. No statistical analysis was made.","Absolute","Decrease",null,null,"ppm",{"$f":"IF(Z170<>0,VLOOKUP(Z170,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","F",null,"Reproductive","Time to mating",{"$f":"IF(Z171<>0,VLOOKUP(Z171,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z171<>0,VLOOKUP(Z171,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",700,"Reproductive","[Not in list]",{"$f":"IF(Z172<>0,VLOOKUP(Z172,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Mating indices (%) were not affected in F0 rats but in F1 males and females in the 700 ppm group they were decreased (down to 53-55% compared to 93% in controls). ","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z172<>0,VLOOKUP(Z172,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M + F",700,"Reproductive","Fertility (mammals)",{"$f":"IF(Z173<>0,VLOOKUP(Z173,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Fertility indices (%) were not affected in F0 rats but were decreased in 700 ppm F1 males and females (77% compared to 100% in controls)","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z173<>0,VLOOKUP(Z173,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","F",700,"Reproductive","Gestation length",{"$f":"IF(Z174<>0,VLOOKUP(Z174,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Gestation length was increased in F1 700ppm rats (22.1 days compared to 21.6 days in controls), but not in F0 rats.","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z174<>0,VLOOKUP(Z174,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","F",null,"Reproductive","Fertility (mammals)",{"$f":"IF(Z175<>0,VLOOKUP(Z175,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Number of non-pregnant F1 rats were increasing with exposure (4/30, 10/30, 9/30, 12/30, 18/30 in control, 70, 300, 500, and 700 ppm group respectively). No statistical assessment was made. ","Absolute","Increase",null,null,"ppm",{"$f":"IF(Z175<>0,VLOOKUP(Z175,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","F",null,"Reproductive","Estrus cyclicity",{"$f":"IF(Z176<>0,VLOOKUP(Z176,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"The number of non-pregnant rats with estrous cycle irregularities\nwas 2/4, 8/10, 5/9, 10/12, and 15/18 in control, 70, 300, 500,\nand 700 ppm groups, respectively. No statistical assessment was made. ","Absolute","Increase",null,null,"ppm",{"$f":"IF(Z176<>0,VLOOKUP(Z176,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","F",null,"Organ histopathology","Ovary histopathology",{"$f":"IF(Z177<>0,VLOOKUP(Z177,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Number of non-pregnant rats with abnormal ovaries and devoid of corpora lutea were increasing with exposure from 2/4, 6/10, 4/9, 5/12 and 13/18 in the control, 70, 300, 500, and 700ppm groups, respectively. No statistical analysis was performed. ","Absolute","Increase",null,null,"ppm",{"$f":"IF(Z177<>0,VLOOKUP(Z177,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","F",null,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z178<>0,VLOOKUP(Z178,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Number of non-pregnant rats with reduced numbers or only old corpora lutea was present in all exposure groups but not in control (0/4, 2/10, 1/9, 5/12, 2/18 for control, 70, 300, 500, 700 ppm, respectively). No statistical analysis was made. ","Absolute",null,null,null,"ppm",{"$f":"IF(Z178<>0,VLOOKUP(Z178,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","F",null,"Reproductive","Estrus cyclicity",{"$f":"IF(Z179<>0,VLOOKUP(Z179,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Number of non-pregnant rats with estrous cycle perturbation increased with exposure from 2/4 in controls to 8/10, 5/9, 10/12, 15/18. No statistical analysis was made. ","Absolute","Increase",null,null,"ppm",{"$f":"IF(Z179<>0,VLOOKUP(Z179,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","F",null,"Organ histopathology","Mammary gland histopathology (female)",{"$f":"IF(Z180<>0,VLOOKUP(Z180,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Number of mammary gland changes with ductal/acinar and/or lobular proliferation with secretory activity was 1, 6, 3, 5, 11 and number of rats with duct ectasia galactocele was 0, 3, 3, 1, 6 in control, 70, 300, 500, 700 ppm D4, respectively (out of groups of 30 animals). No statistical analysis was made. ","Absolute",null,null,null,"ppm",{"$f":"IF(Z180<>0,VLOOKUP(Z180,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)","M",null,"Organ histopathology","Mammary gland histopathology (male)",{"$f":"IF(Z181<>0,VLOOKUP(Z181,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect observed","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z181<>0,VLOOKUP(Z181,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","F",700,"Reproductive","Number of implantations, corpora lutea",{"$f":"IF(Z182<>0,VLOOKUP(Z182,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Number of implantation sites was lower in 700 ppm F0 females (73% of control), whereas this parameter was not affected in F1 females. ","Absolute","Decrease",500,700,"ppm",{"$f":"IF(Z182<>0,VLOOKUP(Z182,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M",70,"Reproductive","Sperm numbers",{"$f":"IF(Z183<>0,VLOOKUP(Z183,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Statistically significant increases in testicular sperm numbers and sperm production\nrate were seen in all F0 exposed groups. However, the concurrent\ncontrol group value for sperm numbers was unusually low\nrelative to contract laboratory historical data and the control\ngroup value for the F1 males. In addition, similar effects were\nnot observed on epididymal sperm numbers and no effects were observed in F1 males","Absolute","Change",null,70,"ppm",{"$f":"IF(Z183<>0,VLOOKUP(Z183,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M",null,"Reproductive","Sperm motility",{"$f":"IF(Z184<>0,VLOOKUP(Z184,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect in any groups of F0 or F1 males","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z184<>0,VLOOKUP(Z184,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)","M",null,"Reproductive","Sperm morphology",{"$f":"IF(Z185<>0,VLOOKUP(Z185,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect in any groups of F0 or F1 males","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z185<>0,VLOOKUP(Z185,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",500,"Reproductive","[Not in list]",{"$f":"IF(Z186<>0,VLOOKUP(Z186,Interpretation!$C:$E,2,FALSE),\"\")","v":"[Not in list]"},"Litter number: The number of litters produced in the F1 generation in the\n700 ppm group for the first mating and in the 500 and 700 ppm\ngroups for the second mating were significantly reduced (59%, 65% and 46% of control, respectively).","Relative (per litter)","Decrease",300,500,"ppm",{"$f":"IF(Z186<>0,VLOOKUP(Z186,Interpretation!$C:$E,3,FALSE),\"\")","v":0}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",500,"Reproductive","Litter viability",{"$f":"IF(Z187<>0,VLOOKUP(Z187,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Litter loss: The number of total litter losses was comparable to controls in the\nF0 litters and all F1 litters (F2a, F2b, and F2c) except in the F0\n500 ppm group where 5 litter losses were observed","Relative (per litter)","Increase",300,500,"ppm",{"$f":"IF(Z187<>0,VLOOKUP(Z187,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",500,"Reproductive","Litter size",{"$f":"IF(Z188<>0,VLOOKUP(Z188,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Reductions in total litter sizes and live pups/litter were observed in the 500 and 700 ppm\ngroups in the F0 generation and for the F1 animals in the first\nmating. No effects were observed on litter size when the F1 males\nwere paired with unexposed females.","Relative (per litter)","Decrease",300,500,"ppm",{"$f":"IF(Z188<>0,VLOOKUP(Z188,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",700,"Reproductive","Pup survival index",{"$f":"IF(Z189<>0,VLOOKUP(Z189,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Pup survival of F2b pups was significantly reduced\n(p < 0.05) in the 700 ppm offspring at PND 0 (87.6% compared to 97.8% in control). No other relevant\neffects on pup survival were noted","Relative (per litter)","Decrease",500,700,"ppm",{"$f":"IF(Z189<>0,VLOOKUP(Z189,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",null,"Reproductive","Sex ratio",{"$f":"IF(Z190<>0,VLOOKUP(Z190,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z190<>0,VLOOKUP(Z190,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",700,"Developmental","Litter/pup weight",{"$f":"IF(Z191<>0,VLOOKUP(Z191,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Mean F1 and F2a pup body weights (both sexes combined)\nwere increased in the 700 ppm group on PND 1 and 4. The increases in pup body weights were\nconsidered to be related to the reduced mean live litter size in the\n700 ppm group.","Absolute","Increase",500,700,"ppm",{"$f":"IF(Z191<>0,VLOOKUP(Z191,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F2)","M",null,"Reproductive","Age at balanopreputial separation",{"$f":"IF(Z192<>0,VLOOKUP(Z192,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z192<>0,VLOOKUP(Z192,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","F",null,"Reproductive","Age at Vaginal opening",{"$f":"IF(Z193<>0,VLOOKUP(Z193,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z193<>0,VLOOKUP(Z193,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Two-generation reproduction toxicity test",8,"Siddiqui et al. 2007","Exposure 6 hours/day following EPA OPPTS Health Effects Test guideline. Exposure at least 70 days prior to mating, during gestation and lactation.","Open literature","Siddiqui et al. 2007",2007,"Rat","Sprague-Dawley","30 (F0) or 23-27 litters (F1)","M + F",0.997,"Inhalation","Whole-Body","70, 300, 500, 700",70,700,"ppm","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)","M + F",null,"Abnormalities","Ano-Genital distance",{"$f":"IF(Z194<>0,VLOOKUP(Z194,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",700,null,"ppm",{"$f":"IF(Z194<>0,VLOOKUP(Z194,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",898,"In life observation","Clinical signs",{"$f":"IF(Z195<>0,VLOOKUP(Z195,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Clinical signs observed in one third of the females in the 898-ppm\ngroup. These clinical signs, consisting of hunched posture and\na slightly stiff gait, were of minor severity and were recorded\nonly occasionally during the rest 8 days of exposure.","Absolute","Increase",488,898,"ppm",{"$f":"IF(Z195<>0,VLOOKUP(Z195,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",898,"In life observation","Mortality",{"$f":"IF(Z196<>0,VLOOKUP(Z196,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Five females in the highest-exposure group died on days 2\n(two animals), 3, 43, and 78. Gross necropsy was unrevealing\nand the cause of death could not be determined.","Absolute","Increase",488,898,"ppm",{"$f":"IF(Z196<>0,VLOOKUP(Z196,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",898,"In life observation","Body weight",{"$f":"IF(Z197<>0,VLOOKUP(Z197,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Body weights of both male and female rats in the 898-ppm group\nwere slightly less (4% to 6%) than controls over the course of\nthe study. Not statistically significant","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z197<>0,VLOOKUP(Z197,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",898,"In life observation","Food consumption",{"$f":"IF(Z198<>0,VLOOKUP(Z198,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"First 3 days of exposure food consumption was decreased in male (20%) and female (28%) in the 898 ppm groups. But food consumption was generally not affected over the remainder of the study. No statistically significant effects.","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z198<>0,VLOOKUP(Z198,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",null,"Organ Weight","Liver weight",{"$f":"IF(Z199<>0,VLOOKUP(Z199,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z199<>0,VLOOKUP(Z199,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",null,"Organ Weight","Thymus weight",{"$f":"IF(Z200<>0,VLOOKUP(Z200,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z200<>0,VLOOKUP(Z200,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",488,"Organ Weight","Kidney weight",{"$f":"IF(Z201<>0,VLOOKUP(Z201,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Increased in the 488 ppm group at 3 months exposure and decreased after 1 months recovery period (10 animals) in the 898 ppm group","Absolute and relative/brain weight","Change",122,488,"ppm",{"$f":"IF(Z201<>0,VLOOKUP(Z201,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",null,"Organ Weight","Adrenals weight",{"$f":"IF(Z202<>0,VLOOKUP(Z202,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Decreased absolute (not relative to brain weight) weight in 898 ppm group after 1 month recovery (10 animals) (93% of control)","Absolute","Decrease",488,898,"ppm",{"$f":"IF(Z202<>0,VLOOKUP(Z202,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",488,"Organ Weight","Testis weight",{"$f":"IF(Z203<>0,VLOOKUP(Z203,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Increased testis weight (117% of control) after 3 months exposure to 488 ppm - no effect was observed at 898 ppm.","Absolute","Increase",122,488,"ppm",{"$f":"IF(Z203<>0,VLOOKUP(Z203,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",488,"Organ Weight","Liver weight",{"$f":"IF(Z204<>0,VLOOKUP(Z204,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Increased in the 488 (120% of control) and 898 (125% of control) ppm groups after 3 months exposure but not after 1 month recovery.","Absolute and relative to brain weight","Increase",122,488,"ppm",{"$f":"IF(Z204<>0,VLOOKUP(Z204,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",488,"Organ Weight","Thymus weight",{"$f":"IF(Z205<>0,VLOOKUP(Z205,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Decreased in 488 (79% of control) and 898 (86% of control) groups. ","Absolute and relative to brain weight","Decrease",122,488,"ppm",{"$f":"IF(Z205<>0,VLOOKUP(Z205,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",null,"Organ Weight","Kidney weight",{"$f":"IF(Z206<>0,VLOOKUP(Z206,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"No effect","Absolute and relative","No effect",898,null,"ppm",{"$f":"IF(Z206<>0,VLOOKUP(Z206,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",488,"Organ Weight","Adrenals weight",{"$f":"IF(Z207<>0,VLOOKUP(Z207,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"Increased in 488 (117% of control) and 898 (129% of control) groups. ","Absolute and relative","Increase",122,488,"ppm",{"$f":"IF(Z207<>0,VLOOKUP(Z207,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",898,"Organ Weight","Ovary weight",{"$f":"IF(Z208<>0,VLOOKUP(Z208,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Decreased in the 898 ppm exposure group (62% of control). But no effect was observed in animals that was allowed 1 month recovery (10 animals)","Absolute and relative to brain weight","Decrease",488,898,"ppm",{"$f":"IF(Z208<>0,VLOOKUP(Z208,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",null,"Organ histopathology","Liver histopathology",{"$f":"IF(Z209<>0,VLOOKUP(Z209,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"No treatment -related effects were observed","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z209<>0,VLOOKUP(Z209,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",898,"Organ histopathology","Vagina histopathology",{"$f":"IF(Z210<>0,VLOOKUP(Z210,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"More female rats from the\n898-ppm exposure group appeared to be in the diestrus stage of the rat estrous cycle (18/20 rats compared to 9/20 in control). No statistical analysis was made. At the end of\nthe 1-month recovery phase, the estrous cycle, as reflected by\nthe vaginal changes in the control and highest-exposure group,\nwere similar","Absolute","Increase",488,898,"ppm",{"$f":"IF(Z210<>0,VLOOKUP(Z210,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",898,"Organ histopathology","Vagina histopathology",{"$f":"IF(Z211<>0,VLOOKUP(Z211,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Mucification of the vaginal mucosa was increased\nin incidence and the thickness of the mucinous cell layer\nwas more prominent in the 898ppm-exposure group (19/20 rats compared to 9/20 in control). No statistical analysis was made. After 1 month recovery no effects were observed (10 animals/group). ","Absolute","Increase",488,898,"ppm",{"$f":"IF(Z211<>0,VLOOKUP(Z211,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",898,"Organ histopathology","Ovary histopathology",{"$f":"IF(Z212<>0,VLOOKUP(Z212,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Ovarian hypoactivity, meaning absence of corpora lutea; normal follicular development present, was increased in incidence in\nfemale rats from the 898-ppm exposure group (9/20 compared to 1/20 in control). No statistical analysis was carried out. The effect was not observed after 1 month recovery period (10 animals/group). ","Absolute","Increase",488,898,"ppm",{"$f":"IF(Z212<>0,VLOOKUP(Z212,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",null,"Organ histopathology","Adrenals histopathology",{"$f":"IF(Z213<>0,VLOOKUP(Z213,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z213<>0,VLOOKUP(Z213,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",null,"Organ histopathology","Brain histopathology examination",{"$f":"IF(Z214<>0,VLOOKUP(Z214,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z214<>0,VLOOKUP(Z214,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",null,"Organ histopathology","Epididymis histopathology",{"$f":"IF(Z215<>0,VLOOKUP(Z215,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z215<>0,VLOOKUP(Z215,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",null,"Organ histopathology","Liver histopathology",{"$f":"IF(Z216<>0,VLOOKUP(Z216,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z216<>0,VLOOKUP(Z216,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",null,"Organ histopathology","Prostate histopathology (with seminal vesicles and coagulating glands)",{"$f":"IF(Z217<>0,VLOOKUP(Z217,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z217<>0,VLOOKUP(Z217,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",null,"Organ histopathology","Pituitary histopathology",{"$f":"IF(Z218<>0,VLOOKUP(Z218,Interpretation!$C:$E,2,FALSE),\"\")","v":"Sensitive to, but not diagnostic of, EATS"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z218<>0,VLOOKUP(Z218,Interpretation!$C:$E,3,FALSE),\"\")","v":"N"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M",null,"Organ histopathology","Testis histopathology",{"$f":"IF(Z219<>0,VLOOKUP(Z219,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z219<>0,VLOOKUP(Z219,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","M + F",null,"Organ histopathology","Thyroid histopathology",{"$f":"IF(Z220<>0,VLOOKUP(Z220,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z220<>0,VLOOKUP(Z220,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"}]
["Mammals","Chronic toxicity",9,"Burns-Naas et al. 2002","Exposure 6 hours/day, 5 days/week, for 3 months. Approximately 10 weeks of age at initiation of exposure. ","Open literature","Burns-Naas et al. 2002",2002,"Rat","Fischer 344",20,"M + F",">99%","Inhalation","Nose only","0, 35, 122, 488, 898",35,898,"ppm",3,"Months","Adult","F",null,"Organ histopathology","Uterus histopathology (with cervix)",{"$f":"IF(Z221<>0,VLOOKUP(Z221,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"No effect","Absolute","No effect",898,null,"ppm",{"$f":"IF(Z221<>0,VLOOKUP(Z221,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, S"}]
["Mammals","Uterotrophic assay",10,"McKim et al. 2001a","Exposure for 4 days. Fischer rats were 21 days old and Sprague-Dawley 18 days old at initiation of exposure. ","Open literature","McKim et al. 2001a",2001,"Rat","Fischer 344 or Sprague-Dawley",12,"F",">98%","Oral","Gavage/Intubation","0, 10, 50, 100, 250, 500, 1000",10,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",null,"In life observation","Clinical signs",{"$f":"IF(Z222<>0,VLOOKUP(Z222,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"No treatment-related clinical abnormalities observed in any of the treatment groups","Absolute","No effect",1000,null,"mg/kg bw/day",{"$f":"IF(Z222<>0,VLOOKUP(Z222,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Uterotrophic assay",10,"McKim et al. 2001a","Exposure for 4 days. Fischer rats were 21 days old and Sprague-Dawley 18 days old at initiation of exposure. ","Open literature","McKim et al. 2001a",2001,"Rat","Fischer 344 or Sprague-Dawley",12,"F",">98%","Oral","Gavage/Intubation","0, 10, 50, 100, 250, 500, 1000",10,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",1000,"In life observation","Body weight",{"$f":"IF(Z223<>0,VLOOKUP(Z223,Interpretation!$C:$E,2,FALSE),\"\")","v":"Systemic toxicity"},"Sprague-Dawley rats in the 1000 mg group had a statistically significant reduction in\nbody weight on day 21, but not on day 22. Fisher rats had a statistically significant reduction in\nbody weight on day 23, 24, and 25. It was not possible to determine the exact % weight reduction from graphs but no effects were larger than around 10%. ","Absolute","Decrease",500,1000,"mg/kg bw/day",{"$f":"IF(Z223<>0,VLOOKUP(Z223,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Uterotrophic assay",10,"McKim et al. 2001a","Exposure for 4 days. Fischer rats were 21 days old and Sprague-Dawley 18 days old at initiation of exposure. ","Open literature","McKim et al. 2001a",2001,"Rat","Fischer 344 or Sprague-Dawley",12,"F",">98%","Oral","Gavage/Intubation","0, 10, 50, 100, 250, 500, 1000",10,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",500,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z224<>0,VLOOKUP(Z224,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"When 500 mg D4 was co-administered with increasing levels of Ethinyl estradiol (EE), EE-dependent\nuterine growth was decreased by half in Sprague-dawley pups\nand by nearly an order of magnitude in Fischer-344 pups. These data indicate weak antiestrogenic properties of D4.","Absolute","Change",null,500,null,{"$f":"IF(Z224<>0,VLOOKUP(Z224,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"}]
["Mammals","Uterotrophic assay",10,"McKim et al. 2001a","Exposure for 4 days. Fischer rats were 21 days old and Sprague-Dawley 18 days old at initiation of exposure. ","Open literature","McKim et al. 2001a",2001,"Rat","Fischer 344 or Sprague-Dawley",12,"F",">98%","Oral","Gavage/Intubation","0, 10, 50, 100, 250, 500, 1000",10,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",250,"Organ histopathology","Uterus histopathology (UT assay)",{"$f":"IF(Z225<>0,VLOOKUP(Z225,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Uterine epithelium cell height, in both strains of rats, was\nincreased in a dose-related manner following treatment with\nD4 at 250, 500, and 1000 mg/kg/day","Absolute","Increase",100,250,"mg/kg bw/day",{"$f":"IF(Z225<>0,VLOOKUP(Z225,Interpretation!$C:$E,3,FALSE),\"\")","v":"E"},"Ethinyl Estradiol produced a maximal response of approximately 40 µm at 10 µg/kg/day, while the maximum response resulting from D4 was approximately 30 µm at a dose of 1,000,000 µg/kg/day. Based on a point estimate of these\nvalues, EE was about 100,000 times more potent than D4 in both strains of rats"]
["Mammals","Uterotrophic assay",10,"McKim et al. 2001a","Exposure for 4 days. Fischer rats were 21 days old and Sprague-Dawley 18 days old at initiation of exposure. ","Open literature","McKim et al. 2001a",2001,"Rat","Fischer 344 or Sprague-Dawley",12,"F",">98%","Oral","Gavage/Intubation","0, 10, 50, 100, 250, 500, 1000",10,1000,"mg/kg bw/day",4,"Days","[Not in list]","F",250,"Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z226<>0,VLOOKUP(Z226,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"Uterine weight was increased in both rat strains from 250 mg/kg D4 exposure (approximately 30% at 250 mg up to 130% at 1000 mg - increases are approximated from graphs). ","Absolute & relative to bw","Increase",100,250,"mg/kg bw/day",{"$f":"IF(Z226<>0,VLOOKUP(Z226,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"}]
["Mammals","Uterotrophic assay",11,"Hayden and Barlow 1972","Exposure for 3 days of immature ovariectomized rats. ","Open literature","Hayden and Barlow 1972",1972,"Rat","Wistar",6,"F","?","Oral","Gavage/Intubation","?","?","?","mg/kg bw/day",3,"Days","[Not in list]","F","?","Organ Weight","Uterus weight (UT assay)",{"$f":"IF(Z227<>0,VLOOKUP(Z227,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"A statistically non-significant increase <20% was observed following exposure to an unknown dose of D4. ","Relative to bw","Increase","?","?","mg/kg bw/day",{"$f":"IF(Z227<>0,VLOOKUP(Z227,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 4 weeks, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 700",700,700,"ppm",4,"Weeks","Adult","F",700,"Organ Weight","Liver weight",{"$f":"IF(Z228<>0,VLOOKUP(Z228,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Liver-to-body weight ratios were increased by 18, 20, and 22%\nrelative to controls on days 6, 13, and 27, respectively","Relative to bw","Increase",null,700,"ppm",{"$f":"IF(Z228<>0,VLOOKUP(Z228,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 4 weeks, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 700",700,700,"ppm",4,"Weeks","Adult","F",700,"Organ histopathology","Liver histopathology",{"$f":"IF(Z229<>0,VLOOKUP(Z229,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Indices of cell proliferation (BrdU and PCNA) showed a marked increase in hepatic cell\nproliferation (15-22%) that was not sustained at 27 days. The\ngreatest increase in the incorporation of BrdU occurred on day 6 of exposure in the left lateral, right lateral, and median lobes.","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z229<>0,VLOOKUP(Z229,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 5 days, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 7, 30, 70, 150, 300, 700 ",7,700,"ppm",5,"Days","Adult","F",70,"Organ Weight","Liver weight",{"$f":"IF(Z230<>0,VLOOKUP(Z230,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"D4 increased liver weight in a dose-dependent manner.","Relative to bw","Increase",30,70,"ppm",{"$f":"IF(Z230<>0,VLOOKUP(Z230,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 5 days, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 7, 30, 70, 150, 300, 700 ",7,700,"ppm",5,"Days","Adult","F",70,"Organ histopathology","Liver histopathology",{"$f":"IF(Z231<>0,VLOOKUP(Z231,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"Hepatic hyperplasia, measured by BrdU incorporation and PCNA relative\nabundance, increased in an exposure-dependent manner. The lowest exposure concentration of D4\nthat resulted in a statistically significant increase in BrdU incorporation was 70 ppm. For PCNA expression, the values at the low end of the exposure curve were variable and it is unclear from these data at what point dose-related increases begin.","Absolute","Increase",30,70,"ppm",{"$f":"IF(Z231<>0,VLOOKUP(Z231,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 4 weeks, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 700",700,700,"ppm",4,"Weeks","Adult","F",700,"Organ histopathology","Liver histopathology",{"$f":"IF(Z232<>0,VLOOKUP(Z232,Interpretation!$C:$E,2,FALSE),\"\")","v":"Target organ toxicity"},"D4 reduced the number of nuclei (e.g., cells)\nrelative to controls by 9% on day 6, 16% by day 13, and 11%\nby day 27 indicating hepatocellular hypertrophy. Examination of H &\nE-stained sections from D4-treated and control liver supported\nthe presence of hypertrophy; however, there were no other\nlesions that could be attributed to exposure.","Absolute","Decrease",null,700,"ppm",{"$f":"IF(Z232<>0,VLOOKUP(Z232,Interpretation!$C:$E,3,FALSE),\"\")","v":"_"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 4 weeks, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 700",700,700,"ppm",4,"Weeks","Adult","F",700,"Organ Weight","Thyroid weight",{"$f":"IF(Z233<>0,VLOOKUP(Z233,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Exposure to 700 ppm D4 produced a small but statistically significant increase in thyroid weight on day 6 (17%), 13 (18%) and 27 (23%).","Relative to bw","Increase",null,700,"ppm",{"$f":"IF(Z233<>0,VLOOKUP(Z233,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"}]
["Mammals","Mammals Not il list",12,"McKim et al. 2001b","Exposure for 4 weeks, 6h/day, 5days/week. ","Open literature","McKim et al. 2001b",2001,"Rat","Fischer 344",10,"F","?","Inhalation","Whole-Body","0, 700",700,700,"ppm",4,"Weeks","Adult","F",700,"Organ histopathology","Thyroid histopathology",{"$f":"IF(Z234<>0,VLOOKUP(Z234,Interpretation!$C:$E,2,FALSE),\"\")","v":"EATS-mediated"},"Cell proliferation (BrdU incorporation) was increased after 6 (8%) and 13 (7%) days. On day 27, thyroid cell proliferation in D4-treated animals had returned to control values. In a concentration-response experiment with only 6 days of exposure, no effect of D4 was observed on thyroid BrdU incorporation.","Absolute","Increase",null,700,"ppm",{"$f":"IF(Z234<>0,VLOOKUP(Z234,Interpretation!$C:$E,3,FALSE),\"\")","v":"T"}]
["InVitroEstrogen","Other ER in vitro assay",13,"Farasani and Darbre 2016","In vitro, exposure in medium for 21 days","Open literature","Farasani and Darbre et al. 2016",2016,"Human","MCF-10A and MCF-10F cells","3 wells/treatment, 1 experiment",null,0.98,"Uptake from the medium (in vitro)","[Not in list]","0.001, 0.01, 0.1, 1, 10, 100",1E-3,100,"µM",21,"Days","[Not in list]",null,0.01,"Proliferation","Cellular proliferation",{"$f":"IF(Z235<>0,VLOOKUP(Z235,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vitro mechanistic"},"D4 increased cell proliferation statistically significant from 0.01 µM. The increases were larger than the positive control (70 nM 17β-oestradiol) from around 1 µM D4. ","Absolute","Increase",1E-3,0.01,"ppm",{"$f":"IF(Z235<>0,VLOOKUP(Z235,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, T, S"}]
["Mammals","Chronic toxicity",5,"Jean et al. 2017","exposure 5 days/week. 49–50 weeks of age at initiation of exposure.","Open literature","Jean et al. 2017",2017,"Rat","Fischer 344",50,"F",">99%","Inhalation","Whole-Body",700,700,700,"ppm",14,"Months","Adult","F",null,"Clinical chemistry/hormones","Prolactin",{"$f":"IF(Z236<>0,VLOOKUP(Z236,Interpretation!$C:$E,2,FALSE),\"\")","v":"In vivo mechanistic"},"No effects on prolactin levels","Absolute per liter serum","No effect",700,null,"ppm",{"$f":"IF(Z236<>0,VLOOKUP(Z236,Interpretation!$C:$E,3,FALSE),\"\")","v":"E, A, T, S"},null,"Yes","Yes"]

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[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Insert a sorting number (1 .. n) on targets loading as lines of evidence"]
[]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"In vitro mechanistic","In vitro mechanistic","In vitro mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","In vivo mechanistic","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","EATS-mediated","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Sensitive to, but not diagnostic of, EATS","Target organ toxicity","Target organ toxicity","Target organ toxicity","Target organ toxicity","Target organ toxicity","Target organ toxicity","Target organ toxicity","Systemic toxicity","Systemic toxicity","Systemic toxicity","Systemic toxicity","[Not in list]"]
["Study ID Matrix","Source","Year","Type of toxicity","Study Principle","Species","Doses tested","Dose unit","Route of administration","Exposure","Exposure unit","Generation/Life stage","Additional remarks","Relevance","Reliability","Cellular proliferation","Estrogen receptor","Progesterone (in vitro)","Estradiol level","Follicle Stimulating Hormone (FSH) level","LABC weight (Hershberger)","Luteinizing Hormone (LH) level","Other hormones","Phase I enzyme induction (in vivo)","Progesterone","Prolactin","Uterus histopathology (UT assay)","Uterus weight (UT assay)","Age at balanopreputial separation","Age at Vaginal opening","Ano-Genital distance","Cervix histopathology","Epididymis histopathology","Estrus cyclicity","Mammary gland histopathology (female)","Mammary gland histopathology (male)","Ovary histopathology","Ovary weight","Oviduct histopathology","Prostate histopathology (with seminal vesicles and coagulating glands)","Sperm morphology","Sperm motility","Sperm numbers","Testis histopathology","Testis weight","Thyroid histopathology","Thyroid weight","Uterus histopathology (with cervix)","Uterus weight (with cervix)","Vagina histopathology","Adrenals histopathology","Adrenals weight","Brain histopathology examination","Brain weight","Fertility (mammals)","Gestation length","Litter size","Litter viability","Litter/pup weight","Number of implantations, corpora lutea","Number of ovarian follicles","Pituitary histopathology","Pituitary weight","Post implantation loss","Pre implantation loss","Pup survival index","Sex ratio","Time to mating","Kidney histopathology","Kidney weight","Liver histopathology","Liver weight","Lung histopathology","Spleen histopathology","Thymus weight","Body weight","Clinical signs","Food consumption","Mortality","[Not in list]"]
[3,"Open literature",2003,"Mammals","Mammals Not il list","Mouse","1, 10, 50, 100, 250, 500, 1000","mg/kg bw/day","Oral",7,"Days","[Not in list]","Dope-dependent reductions in serum E2 levels. Not statistically assessed. ","Yes","Yes",null,null,null,"Decrease 10 (Serum estradiol was reduced by approximately 50 % by D4 exposure of 1000 mg/kg bw/day. Estradiol levels decreased in a dose-dependent manner from 10 mg/kg bw/day. This was however not statistically assessed. , Absolute & relative)"]
[3,"Open literature",2003,"Mammals","Mammals Not il list","Mouse",1000,"mg/kg bw/day","Oral",7,"Days","[Not in list]",null,"Yes","Yes",null,null,null,"Decrease 1000 (Serum estradiol was reduced in intact, sham-operated and adrenalectomized mice, Absolute)",null,null,null,"Increase 1000 (Serum corticosterone increased in D4-exposed intact and sham-operated mice but not in adrenalectomized mice., Absolute)"]
[3,"Open literature",2003,"Mammals","Uterotrophic assay","Mouse",1000,"mg/kg bw/day","Oral",3,"Days","[Not in list]","Uterine peroxidase activity increased by D4 exposure in a similar manner to E2 exposure (E2 response was double the D4 response)","Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 1000 (Uterine peroxidase activity was increased by D4 exposure, Relative)"]
[3,"Open literature",2003,"Mammals","Uterotrophic assay","Mouse","1, 10, 50, 100, 250, 500, 1000","mg/kg bw/day","Oral",3,"Days","[Not in list]","10 µg/kg E2 increased uterine weight 0.5-fold more than 1000 mg/kg D4. ","Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,null,"Increase 250 (Uterine weight was increased by D4 exposure in a dose-dependent manner from 250 mg/kg. Pre-treatment with the ER antagonist ICI 182,780 blocked this effect (assessed at 1000 mg/kg)., Absolute)"]
[3,"Open literature",2003,"Mammals","Uterotrophic assay","Mouse","250, 500, 1000","mg/kg bw/day","Oral",3,"Days","[Not in list]","D4 increased uterine weights in WT mice but not ERα KO mice. ","Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,null,"No effect (D4 did not induce an increase in uterus weight in Erα KO mice.  , Absolute)"]
[1,"Open literature",2015,"Mammals","Uterotrophic assay","Rat","500, 1000","mg/kg bw/day","Direct",4,"Days","[Not in list]",null,"Yes","Yes",null,null,null,null,null,null,null,null,"Increase 500 (Increased CYP2B1 gene expression (10-fold (500 mg), 30-fold (1000mg) compared to control), Relative to 18S expression)",null,null,null,"No effect (No effect after D4 exposure , Relative to bw)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 1000 (Increased relative liver weight compared to control, statistically significant but slight increase around 10%., Relative to bw)",null,null,null,null,null,null,null,"Change 500 (Increased CaBP-9K gene expression (from 500 mg: 1.5-fold, 1000mg: 2.5-fold), no observable effect on protein expression (for all proteins included: assessed from Western blot, not quantified), decreased PR gene expression (1000 mg: 0.6-fold), increased PR protein expression (from 500mg), and decreased Erα gene expression (from 500 mg: 0.5-fold) and had no observable effect on ERα protein expression., Expression levels relative to stable reference genes or proteins)"]
[2,"Open literature",2007,"Mammals","Uterotrophic assay","Rat",700,"ppm","Inhalation",3,"Days","Adult","Both rat strains showed increased wet and blotted uterine weights after D4 exposure compared to controls. As did weights after exposure to positive controls EE (max 6.5-fold) and genistein (data not shown).","Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,"Increase 700 (D4 exposure resulted in an increase in both the luminal (maximal increase: 2.6-fold compared to control) and glandular epithelial cell height (maximal increase: 1.6-fold compared to control) in both Sprague dawley and Fischer-344 rats., Absolute)","Decrease 700 (D4 mildly (80% of EE control) suppressed the EE-induced increase in uterine weight in Fischer 344 rats, but not in sprague dawley rats., Absolute)"]
[2,"Open literature",2007,"Mammals","Hershberger assay","Rat",700,"ppm","Inhalation",10,"Days","Adult","D4 did not affect any male reproductive organ weights (ventral prostate (fixed or fresh), seminal vesicles, LABC muscle, glans penis, or Cowper's gland), thus did not show androgenic activity. D4 also did not affect TP-induced reproductive weight increases, thus no anti-androgenic effect of D4 was shown. ","Yes","Yes",null,null,null,null,null,"No effect (D4 did not affect ventral prostate (fixed or fresh), seminal vesicles, LABC muscle, glans penis, or Cowper's gland weights, nor affect TP-induced weight increase., Absolute)"]
[4,"Open literature",2017,"Mammals","Combined chronic toxicity/carcinogenicity studies","Rat","10, 30, 150, 700","ppm","Inhalation",24,"Months","Adult","6% weight decrease observed only in males statistically significant at week 97 and necropsy (24 months)","Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 700 (cervical squamous epithelial hyperplasia was observed in 5% (3/60) of high dose females at 24 months (compared to 0% in controls)., Absolute)",null,null,null,null,"Increase 700 (ovarian atrophy presented in 6.7% (4/60) of high dosed females at 24 months (compared to 1.7% in controls). , Absolute)",null,null,null,null,null,null,"No effect (No effect of D4 on testis interstitial cell adenoma, Absolute)","Increase 700 (Testes weight increase was observed at 12- and 24-month exposure periods for males exposed to 700 ppm D4. , Relative)","No effect (No statistically significant effects on the incidence of thyroid gland c-cell neoplasia., Absolute)",null,"No effect (No statistically  significant effect of D4 on incidence of uterine neoplasia, Absolute)","Increase 700 (Uterine weight (absolute and relative) was increased (24%) in the 700 ppm exposure group at 24 months. , Absolute and relative)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 30 (The incidence of chronic nephropathy was elevated at 24 months for females at≥ 30 ppm., Absolute)","Increase 150 (The 700 ppm exposure increased male and female kidney weight (absolute and relative) after 12 and 24 months. In the 150 ppm exposure group, female but not male rats also showed increased kidney weights at 24 months. , Absolute and relative)","Increase 700 (increased incidence of centrilobular hypertrophy in males and a reduction in basophilic foci in females at 700 ppm at 12 and 24 months., Absolute)","Increase 30 (Liver weight increases were evident at 6, 12, and 24-months exposure for both sexes. For males, the liver weight increases were associated with exposure to ≥ 30 ppm D4 at 6 months, ≥150 ppm at 12 months, and 700 ppm D4 at 24-months. Female liver weight increases were statistically significant at all three time points (6, 12, and 24 months) at 700 ppm and at 12 and 24 months with exposure to 150 ppm D4. , Absolute and relative)",null,"Increase 30 (increased incidence of hematopoietic proliferation in\nthe spleen of 700 ppm females and 30 ppm males at 24 months, Absolute)",null,"Decrease 700 (Exposure had no effect on body weight or body weight gain with the exception of 700 ppm males in the 24-month exposure group. Mean body weight for this group remained approximately 6% lower than controls for the last few months on study. Statistically significant only for week 97 and at necropsy (month 24), Absolute)"]
[5,"Open literature",2017,"Mammals","Chronic toxicity","Rat",700,"ppm","Inhalation",14,"Months","Adult",null,"Yes","Yes",null,null,null,"Decrease 700 (Decreased serum estradiol over the entire study period, Absolute per liter serum)","No effect 700 (12% lower serum FSH levels at necropsy but no statistical significance, Absolute per liter serum)",null,null,null,null,"Increase 700 (Increased serum progesterone from week 2-10 out of 57 weeks, Absolute per liter serum)",null,null,null,null,null,null,null,null,"Increase 700 (Increased duration of proestrous/estrous phases (2.4-3.5 days/cycle compared to control with 1-2 days/cycle), Absolute)",null,null,"Decrease 700 (Decrease (37%) in the incidence of antral-size atretic follicles in the ovaries, Absolute)","No effect 700 (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,null,"Increase 700 (An increased incidence of cystic endometrial hyperplasia was observed (14/37 compared to control with 8/37), Absolute)","No effect 700 (No effect, Absolute and relative)","Change 700 (D4-exposed animals also had a slightly lower incidence of vaginal mucification than controls – but for those animals in the D4-group that did display mucification there was a shift to moderate and severe severity.)",null,"No effect 700 (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 700 (Absolute (10%) and relative to bw (8%) increase in kidney weight)",null,"Increase 700 (Absolute (35%) and relative to bw (33%) increase in liver weight)",null,null,null,"No effect (No treatment related effect in body weight, Absolute)",null,null,null,"Decrease 700 (Decreased (10-30%) corticosterone levels were observed from weeks 2-51 out of 57 weeks. , Absolute per liter serum)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat","70, 300, 500, 700","ppm","Inhalation",37,"Days","Adult",null,"Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,"Increase 700 (Mean absolute maternal adrenal gland weight was increased in high dose group (16.8% compared to control), Absolute)",null,"No effect (No effect, Absolute and relative)","No effect (No effect of D4 on fertility indices compared to control, Absolute)",null,null,"Decrease 500 (Number of viable fetuses was decreased in 500 and 700 ppm groups, Absolute)",null,"Decrease 300 (Decreased number of corpora lutea in 300 (90% of control) and 500 (87% of control) ppm groups. Decreased number of implantation sites in 500 (79% of control) and 700 (68% of control) ppm groups, Absolute)",null,null,null,"No effect (No statistically significant effect on % post-implantation loss in D4 groups, but absolute number increased with exposure from 500 ppm D4 (control 7.8%, 30 ppm D4 6.1%, 300ppm D4 7.5, 500 ppm D4 11.3%, 700 ppm D4 16.6%), Absolute)","Increase 700 (Increased % pre-implantation loss in 700 ppm group, Absolute)",null,null,"No effect (No effect, Absolute)",null,null,null,null,null,null,null,"Decrease 700 (Lower mean body weight gain during gestation (86% of control), Absolute)","No effect (No treatment related clinical signs were observed, Absolute)",null,null,"Decrease 700 (Gravid uterine weight decreased after 700 ppm D4 exposure, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation",28,"Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,"No effect (No effect on gravid uterine weight, Absolute)",null,null,"No effect (No effect, Absolute and relative)",null,"No effect (No effect, Absolute and relative)",null,null,null,"No effect (No effect, Absolute)",null,"No effect (No effect, Absolute)",null,null,null,"No effect (No effect, Absolute)","No effect (No effect, Absolute)",null,null,"No effect (No effect, Absolute)",null,null,null,null,null,null,null,"No effect (No effect on maternal body weight gain during gestation, Absolute)","No effect (No treatment related clinical signs were observed, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation",6,"Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Mean absolute maternal ovary weight was decreased in the 700 ppm group by 10.1% compared to control, Absolute)",null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,"No effect (No effect, Absolute and relative)",null,"No effect (No effect, Absolute and relative)",null,null,null,"Decrease 700 (Decreased number of viable fetuses in D4 group (61% of control)., Absolute)",null,"Decrease 700 (Number of corpora lutea decreased in D4 group (85% of control). Number of implantation sites decreased (69% of control), Absolute)",null,null,null,"Increase 700 (Increased post-implantation loss in D4 group (18%) compared to control (6.4%). , Absolute)","Increase 700 (Increased in D4 group (28.4%) compared to control (9.8%)., Absolute)",null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Lower mean body weight gain during gestation (87% of control), Absolute)","No effect (No exposure-related clinical signs were observed, Absolute)",null,null,"Decrease 700 (Gravid uterine weight decreased after 700 ppm D4 exposure, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation",4,"Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,"No effect (No effect, Absolute and relative)",null,"No effect (No effect, Absolute and relative)",null,null,null,"No effect (No effect, Absolute)",null,"No effect (No effect, Absolute)",null,null,null,"No effect (No effect, Absolute)","No effect (No effect, Absolute)",null,null,null,null,null,null,null,null,null,null,null,"Change (Observed in both control group and D4 exposed group, Absolute)",null,null,"No effect (No effect on gravid uterine weight, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation",1,"Day","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Fertility index decreased after D4 exposure 1 day before mating (64.7%) compared to control (95.5%). , Absolute)",null,null,null,null,"No effect (No effect of exposure on corpora lutea or number of implantation sites, Absolute)",null,null,null,null,"No effect (No effect on % pre-implantation loss, Absolute)",null,null,null,null,null,null,null,null,null,null,"No effect (No effect on maternal GD0-8 body weight gain, Absolute)",null,null,null,"No effect (No effect on gravid uterine weight, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-04-06","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 700 (Increased maternal GD0-8 body weight gain (128% of control) in the 'day -3 to GD1' exposure group., Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-04-06","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect on fertility index (%), Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-04-06","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Decreased gravid uterine weight in 'day -3 to GD3' exposure group, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-04-06","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Decreased number of corpora lutea in 'day -3 to GD3' exposure group (87% of control). No statistically significant effect on number of implantation sites. , Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-04-06","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect on % pre-implantation loss, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-01-03","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect of short post-mating exposure on fertility index (%), Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-01-03","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect of short post-mating exposure on gravid uterine weight, Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-01-03","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect of short post-mating exposure on number of corpora lutea or number of implantation sites , Absolute)"]
[6,"Open literature",2007,"Mammals","Mammals Not il list","Rat",700,"ppm","Inhalation","2021-01-03","Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect of short post-mating exposure on % pre-implantation loss , Absolute)"]
[7,"Open literature",2007,"Mammals","Mammals Not il list","Rat","700, 900","ppm","Inhalation","2,1","Days","Adult",null,null,null,null,null,null,"Increase 700 (Increases in plasma estrone levels but not estradiol or estrone/estradiol ratios were observed at 700 and 900 ppm, Absolute)","No effect (No effect, Absolute)",null,null,null,null,"Increase 900 (Increased plasma progesterone levels in 900 ppm group, Absolute)",null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,"No effect (No effect, Absolute and relative)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Reductions in mean terminal body weight occurred in both treatment groups, relative to controls (252±2.7 and 255±2.1 g, respectively, versus 263±2.5 g), Absolute)"]
[7,"Open literature",2007,"Mammals","Mammals Not il list","Rat","700, 900","ppm","Inhalation",3,"Days","Adult",null,null,null,null,null,null,"Increase 700 (Mean plasma E2 levels on the morning of estrous were elevated\nin the 700 and 900 ppm exposure groups (22.2±4.3 and\n21.2±1.8 pg/mL, respectively) compared to the control group\n(7.76±1.4 pg/mL). Plasma E1 levels in D4-treated rats were significantly\nhigher in both the 700 (72.0±3.4 pg/mL) and 900 ppm\n(79.1±4.4 pg/mL) exposure groups relative to controls\n(51.5±3.1 pg/mL). Statistically significant\nreductions in E1/E2 ratios were observed both in the 700\nand 900 ppm exposure groups relative to the plasma E1/E2\nratios in control rats., Absolute)","Decrease 700 (Mean plasma FSH levels on the morning of estrous were decreased after both 700 and 900 ppm D4 exposure, Absolute)",null,"Decrease 700 (Plasma LH levels were lower than controls at the 4, 6, and 8 p.m. time points\nin the 700 ppm exposure group, achieving a significant reduction\nonly at the 6 p.m. time point (7.9±1.7 ng/mL compared with\n14.2±2.2 ng/mL in the controls) (Fig. 4). Significantly lower\nLH levels were observed at the 4, 6, and 8 p.m. measurements\nin the 900 ppm exposure group (Fig. 4). The area under the LH\ncurve was also significantly less in the 900 ppm group, but not\nin the 700 ppm group, relative to controls. When grouped by ovulatory status, ovulating or non-ovulating rats, there were no treatment-related differences in\nthe mean plasma LH levels. Every animal that failed to produce an LH surge failed to ovulate., Absolute)",null,null,"No effect (No effects on progesterone levels on the morning of estrous, Absolute)","Decrease 700 (Reduction in PRL levels was noted only at the\n2 p.m. time point in both exposure groups (time points: 2, 4, 6, 8, 10 p.m.), Absolute)",null,null,null,null,null,null,null,null,null,null,null,"Decrease 900 (Decreased ovarian weight was observed in the 900 ppm group, both absolute and relative to body weight and brain weight, Absolute and relative)","No effect (No change in the number of Corpora lutea was detectable among ovulating rats, Absolute)",null,null,null,null,null,null,null,null,null,"Decrease 900 (Decreased uterus/body weight in 900 ppm group compared to control, Relative)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 900 (Reduction in mean terminal body weight was observed only at 900 ppm\n(260±3.0 g versus 270±2.2 g in control), Absolute)",null,null,null,"Decrease 700 (Exposure to D4 at 700 and 900 ppm significantly decreased the proportion of rats\nthat ovulated (79% of controls, 42% of 700 ppm, and 31% of 900 ppm exposed rats)., Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","107-125","Days","Adult (F0)","Two cases of death due to dystocia of females in the high exposure group. ",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (Mean weekly body weight were comparable between groups., Absolute)","No effect (No exposure-related clinical signs were observed, Absolute)","Decrease 700 (Food consumption and mean body weight gain was reduced in week 1 of exposure in 700 ppm males, Absolute)",null,"Change (Ejaculatory plug production increased with exposure and was 0.033, 0.023, 0.058, 0.332 and 0.600 plugs/rat/day in the 0, 70, 300, 500 and 700 ppm groups,\nrespectively. No statistical analysis was performed., Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","≥138 days","Days","Adult (F1)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (Maternal body weight gain during gestation was reduced in 700 ppm females (104g compared to 126g in control group). This may be the result of the reduced number of pups., Absolute)","No effect (No exposure-related clinical signs were observed, Absolute)","Decrease 700 (Food consumption and mean body weight gain was reduced in week 1 of exposure in 700 ppm males, Absolute)",null,"Change (Ejaculatory plug production increased with exposure and was 0.027, 0.030, 0.052, 0.112 and 0.425 plugs/rat/day in the 0, 70, 300, 500 and 700 ppm groups,\nrespectively. No statistical analysis was performed., Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","Indirect during gestation and lactation","Days","Offspring (F2)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No exposure-related clinical signs were observed, Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect on ovary weight, Absolute and relative)",null,null,"No effect (No effect in any groups of F0 or F1 males, Absolute)","No effect (No effect in any groups of F0 or F1 males, Absolute)","Change 70 (Statistically significant increases in testicular sperm numbers and sperm production\nrate were seen in all F0 exposed groups. However, the concurrent\ncontrol group value for sperm numbers was unusually low\nrelative to contract laboratory historical data and the control\ngroup value for the F1 males. In addition, similar effects were\nnot observed on epididymal sperm numbers and no effects were observed in F1 males, Absolute)",null,"No effect (No effect on left or right testis weight, Absolute and relative)",null,null,null,null,null,null,null,null,null,"Decrease 700 (Fertility indices (%) were not affected in F0 rats but were decreased in 700 ppm F1 males and females (77% compared to 100% in controls), Absolute)","Increase 700 (Gestation length was increased in F1 700ppm rats (22.1 days compared to 21.6 days in controls), but not in F0 rats., Absolute)",null,null,null,"Decrease 700 (Number of implantation sites was lower in 700 ppm F0 females (73% of control), whereas this parameter was not affected in F1 females. , Absolute)",null,null,"Increase 700 (Increased relative pituitary weight in F0 700 ppm males (OBS! the table in the paper reports the same values for control and exposed). Absolute and relative pituitary weight in F1 700 ppm females was increased (33-40%). , Absolute and relative)",null,null,null,null,"No effect (No effect, Absolute)","Increase 700 (Increased incidence of tubular mineralization in kidneys from 700 ppm exposed F0 and F1 males (data not shown). , Absolute)","Increase 300 (Relative kidney weights were increased in F0 males from 300 ppm (8%-15%), absolute from 500 ppm (8-11%). For F1 males only relative kidney weights were increased (9-11%) from 500 ppm D4 exposure. In females only 700 ppm D4 in F1 females increased the absolute (13%) and relative (9%) kidney weight., Absolute and relative)","Increase 700 (The incidence of pigment in the liver was increased in 700 ppm F1 males. The\npigment was extracellular in periportal regions and morphologically\ncompatible with bile pigment. The incidence of bile duct\nhyperplasia was increased in 700 ppm F1 males, Absolute)","Increase 300 (Increased relative liver weight (9-18.5%) in 300, 500, and 700 ppm males, also absolute weight in 700 ppm males (16%). In F0 females, absolute and relative liver weights were increased (9-33%) after 300, 500, and 700 ppm D4 exposure. For F1 females, absolute and relative liver weights were increased (14-33%) after 500 and 700 ppm D4. , Absolute and relative)","Increase 700 (Significant increases in the incidence of focal alveolar histiocytosis were noted in the\nlungs of 700 ppm F0 and F1 females and the F1 males., Absolute)",null,null,null,null,null,null,"Decrease 700 (Mating indices (%) were not affected in F0 rats but in F1 males and females in the 700 ppm group they were decreased (down to 53-55% compared to 93% in controls). , Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat",700,"ppm","Inhalation","107-125 (F0) ","Days","Adult (F0)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No evidence of exposure-related effects, Absolute)","No effect (No evidence of exposure-related effects, Absolute)",null,"No effect (No evidence of exposure-related effects, Absolute)",null,null,null,null,null,null,null,null,null,null,"No effect (No evidence of exposure-related effects, Absolute)",null,"No effect (No evidence of exposure-related effects, Absolute)",null,null,null,null,null,null,null,null,null,null,null,"No effect (No evidence of exposure-related effects, Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat",700,"ppm","Inhalation","107-125 (F0) or ≥138 days (F1)","Days","Adult (F0+F1)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No treatment-related differences in ovarian primordial follicle counts or number of sections with growing follicles present. , Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation"," ≥138 days (F1)","Days","Adult (F1)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 700 (15/30 females in the 700 ppm group were anovulatory or had abnormal estrous cycles (5.3 days compared to 4.2 in controls), Absolute)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease (Number of rats with corpora lutea of pregnancy\nwas 26/30, 20/30, 21/30, 18/30, and 12/30 rats in the control,\n70, 300, 500, and 700 ppm groups, respectively. No statistical analysis was made., Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","107-125 (F0) or ≥138 days (F1)","Days","Adult (F1)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase (Number of non-pregnant rats with estrous cycle perturbation increased with exposure from 2/4 in controls to 8/10, 5/9, 10/12, 15/18. No statistical analysis was made. , Absolute)"," (Number of mammary gland changes with ductal/acinar and/or lobular proliferation with secretory activity was 1, 6, 3, 5, 11 and number of rats with duct ectasia galactocele was 0, 3, 3, 1, 6 in control, 70, 300, 500, 700 ppm D4, respectively (out of groups of 30 animals). No statistical analysis was made. , Absolute)","No effect (No effect observed, Absolute)","Increase (Number of non-pregnant rats with abnormal ovaries and devoid of corpora lutea were increasing with exposure from 2/4, 6/10, 4/9, 5/12 and 13/18 in the control, 70, 300, 500, and 700ppm groups, respectively. No statistical analysis was performed. , Absolute)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase (Number of non-pregnant rats were increasing with exposure (4/30, 10/30, 9/30, 12/30, 18/30 in control, 70, 300, 500, and 700 ppm group respectively). No statistical assessment was made. , Absolute)",null,null,null,null," (Number of non-pregnant rats with reduced numbers or only old corpora lutea was present in all exposure groups but not in control (0/4, 2/10, 1/9, 5/12, 2/18 for control, 70, 300, 500, 700 ppm, respectively). No statistical analysis was made. , Absolute)"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F1+F2)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute)","No effect (No effect, Absolute)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 500 (Reductions in total litter sizes and live pups/litter were observed in the 500 and 700 ppm\ngroups in the F0 generation and for the F1 animals in the first\nmating. No effects were observed on litter size when the F1 males\nwere paired with unexposed females., Relative (per litter))","Increase 500 (Litter loss: The number of total litter losses was comparable to controls in the\nF0 litters and all F1 litters (F2a, F2b, and F2c) except in the F0\n500 ppm group where 5 litter losses were observed, Relative (per litter))","Increase 700 (Mean F1 and F2a pup body weights (both sexes combined)\nwere increased in the 700 ppm group on PND 1 and 4. The increases in pup body weights were\nconsidered to be related to the reduced mean live litter size in the\n700 ppm group., Absolute)",null,null,null,null,null,null,"Decrease 700 (Pup survival of F2b pups was significantly reduced\n(p < 0.05) in the 700 ppm offspring at PND 0 (87.6% compared to 97.8% in control). No other relevant\neffects on pup survival were noted, Relative (per litter))","No effect (No effect, Absolute)",null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 500 (Litter number: The number of litters produced in the F1 generation in the\n700 ppm group for the first mating and in the 500 and 700 ppm\ngroups for the second mating were significantly reduced (59%, 65% and 46% of control, respectively)., Relative (per litter))"]
[8,"Open literature",2007,"Mammals","Two-generation reproduction toxicity test","Rat","70, 300, 500, 700","ppm","Inhalation","107-125 (F0) or ≥138 days (F1)","Days","Offspring (F2)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute)"]
[9,"Open literature",2002,"Mammals","Chronic toxicity","Rat","0, 35, 122, 488, 898","ppm","Inhalation",3,"Months","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"No effect (No effect, Absolute)",null,null,null,"Increase 898 (Ovarian hypoactivity, meaning absence of corpora lutea; normal follicular development present, was increased in incidence in\nfemale rats from the 898-ppm exposure group (9/20 compared to 1/20 in control). No statistical analysis was carried out. The effect was not observed after 1 month recovery period (10 animals/group). , Absolute)","Decrease 898 (Decreased in the 898 ppm exposure group (62% of control). But no effect was observed in animals that was allowed 1 month recovery (10 animals), Absolute and relative to brain weight)",null,"No effect (No effect, Absolute)",null,null,null,"No effect (No effect, Absolute)","Increase 488 (Increased testis weight (117% of control) after 3 months exposure to 488 ppm - no effect was observed at 898 ppm., Absolute)","No effect (No effect, Absolute)",null,"No effect (No effect, Absolute)",null,"Increase 898 (Muci\u008efication of the vaginal mucosa was increased\nin incidence and the thickness of the mucinous cell layer\nwas more prominent in the 898ppm-exposure group (19/20 rats compared to 9/20 in control). No statistical analysis was made. After 1 month recovery no effects were observed (10 animals/group). , Absolute)","No effect (No effect, Absolute)","Increase 488 (Increased in 488 (117% of control) and 898 (129% of control) groups. , Absolute and relative)","No effect (No effect, Absolute)",null,null,null,null,null,null,null,null,"No effect (No effect, Absolute)",null,null,null,null,null,null,null,"No effect (No effect, Absolute and relative)","No effect (No effect, Absolute)","Increase 488 (Increased in the 488 (120% of control) and 898 (125% of control) ppm groups after 3 months exposure but not after 1 month recovery., Absolute and relative to brain weight)",null,null,"Decrease 488 (Decreased in 488 (79% of control) and 898 (86% of control) groups. , Absolute and relative to brain weight)","No effect 898 (Body weights of both male and female rats in the 898-ppm group\nwere slightly less (4% to 6%) than controls over the course of\nthe study. Not statistically significant, Absolute)","Increase 898 (Clinical signs observed in one third of the females in the 898-ppm\ngroup. These clinical signs, consisting of hunched posture and\na slightly stiff gait, were of minor severity and were recorded\nonly occasionally during the \u008e rest 8 days of exposure., Absolute)","No effect 898 (First 3 days of exposure food consumption was decreased in male (20%) and female (28%) in the 898 ppm groups. But food consumption was generally not affected over the remainder of the study. No statistically significant effects., Absolute)","Increase 898 (Five females in the highest-exposure group died on days 2\n(two animals), 3, 43, and 78. Gross necropsy was unrevealing\nand the cause of death could not be determined., Absolute)"]
[10,"Open literature",2001,"Mammals","Uterotrophic assay","Rat","0, 10, 50, 100, 250, 500, 1000","mg/kg bw/day","Oral",4,"Days","[Not in list]",null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 250 (Uterine epithelium cell height, in both strains of rats, was\nincreased in a dose-related manner following treatment with\nD4 at 250, 500, and 1000 mg/kg/day, Absolute)","Increase 250 (Uterine weight was increased in both rat strains from 250 mg/kg D4 exposure (approximately 30% at 250 mg up to 130% at 1000 mg - increases are approximated from graphs). , Absolute & relative to bw)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 1000 (Sprague-Dawley rats in the 1000 mg group had a statistically significant reduction in\nbody weight on day 21, but not on day 22. Fisher rats had a statistically significant reduction in\nbody weight on day 23, 24, and 25. It was not possible to determine the exact % weight reduction from graphs but no effects were larger than around 10%. , Absolute)","No effect (No treatment-related clinical abnormalities observed in any of the treatment groups, Absolute)"]
[11,"Open literature",1972,"Mammals","Uterotrophic assay","Rat","?","mg/kg bw/day","Oral",3,"Days","[Not in list]",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase ? (A statistically non-significant increase <20% was observed following exposure to an unknown dose of D4. , Relative to bw)"]
[12,"Open literature",2001,"Mammals","Mammals Not il list","Rat","0, 700","ppm","Inhalation",4,"Weeks","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 700 (Cell proliferation (BrdU incorporation) was increased after 6 (8%) and 13 (7%) days. On day 27, thyroid cell proliferation in D4-treated animals had returned to control values. In a concentration-response experiment with only 6 days of exposure, no effect of D4 was observed on thyroid BrdU incorporation., Absolute)","Increase 700 (Exposure to 700 ppm D4 produced a small but statistically significant increase in thyroid weight on day 6 (17%), 13 (18%) and 27 (23%)., Relative to bw)",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Decrease 700 (D4 reduced the number of nuclei (e.g., cells)\nrelative to controls by 9% on day 6, 16% by day 13, and 11%\nby day 27 indicating hepatocellular hypertrophy. Examination of H &\nE-stained sections from D4-treated and control liver supported\nthe presence of hypertrophy; however, there were no other\nlesions that could be attributed to exposure., Absolute)","Increase 700 (Liver-to-body weight ratios were increased by 18, 20, and 22%\nrelative to controls on days 6, 13, and 27, respectively, Relative to bw)"]
[12,"Open literature",2001,"Mammals","Mammals Not il list","Rat","0, 7, 30, 70, 150, 300, 700 ","ppm","Inhalation",5,"Days","Adult",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Increase 70 (Hepatic hyperplasia, measured by BrdU incorporation and PCNA relative\nabundance, increased in an exposure-dependent manner. The lowest exposure concentration of D4\nthat resulted in a statistically significant increase in BrdU incorporation was 70 ppm. For PCNA expression, the values at the low end of the exposure curve were variable and it is unclear from these data at what point dose-related increases begin., Absolute)","Increase 70 (D4 increased liver weight in a dose-dependent manner., Relative to bw)"]
[2,"Open literature",2007,"InVitroEstrogen","ER Binding Assay","Human",900,"ppm","[Not in list]",4,"Hours",null,"Weak binding of D4 on ERα (ss) (20% inhibition of estradiol binding at 900 ppm (0.45uM), which was the maximal achievable vapor concentration). Diethylstilbestrol applied at 500nM resulted in almost 100% inhibition of estradiol binding.","Yes","Yes",null,"Increase 900 (D4 bound Erα, inhibiting estradiol binding with 20%, Absolute)"]
[2,"Open literature",2007,"InVitroEstrogen","Other ER in vitro assay","Human","0.0001 - 10","µM","Uptake from the medium (in vitro)","?","?",null,"The ERα reporter gene assay showed a 5-fold induction of reporter gene at 10 µM D4 (highest tested concentration). Estradiol induced 35-fold at 10 nM, BPA 10-fold at 20µM.","Yes","Yes",null,"Increase 10 (D4 increased ERα reporter gene activation by 5-fold in MCF-7 cells, Relative)"]
[3,"Open literature",2003,"InVitroEstrogen","ER Binding Assay","Human","1.0 × 10−10 - 1.0 × 10−4","Molar","[Not in list]",30,"Minutes",null,null,null,null,null,"Increase 4.0 × 10−5  (D4 decreased E2 binding to ERα (approximately by 25%) but not Erβ indicating a competitive binding of D4 to Erα. , Absolute)"]
[13,"Open literature",2016,"InVitroEstrogen","Other ER in vitro assay","Human","0.001, 0.01, 0.1, 1, 10, 100","µM","Uptake from the medium (in vitro)",21,"Days","[Not in list]",null,null,null,"Increase 0,01 (D4 increased cell proliferation statistically significant from 0.01 µM. The increases were larger than the positive control (70 nM 17β-oestradiol) from around 1 µM D4. , Absolute)"]
[1,"Open literature",2015,"InVitroEstrogen","Other ER in vitro assay","Rat","1.0 × 10−5 ","Molar","Uptake from the medium (in vitro)",1,"Days","[Not in list]","Direction of effects similar to effects of E2 exposure on CaBP-9K (E2 approx. 50-fold increase in gene expression compared to control), Erα (E2 approx. 0.7-fold gene expression compared to control) and PR (E2 approx. 4.5-fold increase in gene expression compared to control) gene and protein expression. Pre-incubation with ERα inhibitor ICI blocked the effects. Protein expression is not quantified.","Yes","Yes",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Change 1.0 × 10−5  (Increased CaBP-9K (10-fold gene expression compared to control), decreased Erα (0.6-fold gene expression) and increased PR (1.5-fold gene expression) gene and protein expression. , Expression levels relative to stable reference genes or proteins)"]
[2,"Open literature",2007,"InVitroGeneral","In vitro method (general)","Human",900,"ppm","[Not in list]",4,"Hours",null,null,"Yes","Yes",null,null,"No effect (D4 did not affect PRα and β, Absolute)"]
[2,"Open literature",2007,"InVitroGeneral","In vitro method (general)","Human","0.0001 - 10","µM","Uptake from the medium (in vitro)","?","?",null,null,"Yes","Yes",null,null,"No effect (D4 did not affect PRα and β reporter gene activity, Relative)"]
[2,"Open literature",2007,"InVitroGeneral","In vitro method (general)","Human","0.0001 - 1","Molar","Uptake from the medium (in vitro)","?","?",null,null,"Yes","Yes",null,null,"No effect (D4 did not affect PRα in HitHunter assay, Relative)"]
[]
[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Cellular proliferation","Estrogen receptor","Progesterone (in vitro)","Estradiol level","Follicle Stimulating Hormone (FSH) level","LABC weight (Hershberger)","Luteinizing Hormone (LH) level","Other hormones","Phase I enzyme induction (in vivo)","Progesterone","Prolactin","Uterus histopathology (UT assay)","Uterus weight (UT assay)","Age at balanopreputial separation","Age at Vaginal opening","Ano-Genital distance","Cervix histopathology","Epididymis histopathology","Estrus cyclicity","Mammary gland histopathology (female)","Mammary gland histopathology (male)","Ovary histopathology","Ovary weight","Oviduct histopathology","Prostate histopathology (with seminal vesicles and coagulating glands)","Sperm morphology","Sperm motility","Sperm numbers","Testis histopathology","Testis weight","Thyroid histopathology","Thyroid weight","Uterus histopathology (with cervix)","Uterus weight (with cervix)","Vagina histopathology","Adrenals histopathology","Adrenals weight","Brain histopathology examination","Brain weight","Fertility (mammals)","Gestation length","Litter size","Litter viability","Litter/pup weight","Number of implantations, corpora lutea","Number of ovarian follicles","Pituitary histopathology","Pituitary weight","Post implantation loss","Pre implantation loss","Pup survival index","Sex ratio","Time to mating","Kidney histopathology","Kidney weight","Liver histopathology","Liver weight","Lung histopathology","Spleen histopathology","Thymus weight","Body weight","Clinical signs","Food consumption","Mortality","[Not in list]"]
["Effect",null,null,null,null,null,null,null,null,null,null,null,null,null,null,1,3,0,5,1,0,1,1,1,2,1,2,6,0,0,0,1,0,6,0,0,4,3,1,0,0,0,1,1,2,1,1,2,2,4,0,3,0,0,3,1,1,3,1,5,0,0,1,1,2,1,0,0,2,4,6,7,1,1,1,8,2,2,1,12]
["No effect",null,null,null,null,null,null,null,null,null,null,null,null,null,null,0,0,3,0,2,1,0,0,0,1,0,0,2,1,1,1,0,1,1,1,1,1,6,1,1,1,1,0,2,1,2,4,3,3,1,1,4,1,5,3,0,0,2,0,4,1,2,0,3,5,0,1,3,0,1,2,1,0,0,1,6,7,1,0,3]
["Not classified",null,null,null,null,null,null,null,null,null,null,null,null,null,null,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,1,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0]

{"sheet":"LoE females AOs","index":11,"n_rows":91,"n_cols":14,"rows_kept":91,"cut":false,"hidden":false,"merged":[[81,11,87,11],[1,12,90,12],[12,11,17,11],[28,11,32,11],[33,11,36,11],[37,11,41,11],[4,11,9,11],[10,11,11,11],[18,11,26,11],[78,11,80,11],[70,11,76,11],[66,11,69,11],[55,11,64,11],[50,11,54,11],[42,11,47,11]]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[8,"EATS-mediated","Age at Vaginal opening","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","1/1 study found no effect on pubertal timing after developmental exposure (70-700 ppm). ","Evidence for effects on female reproduction including effects on estrous cycle, ovary histopathology and weight, uterus histopathology, vagina histopathology, pregnancy parameters, and fertility. "]
[8,"EATS-mediated","Ano-Genital distance","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","1/1 study found no effect on AGD after developmental exposure (70-700 ppm). "]
[4,"EATS-mediated","Cervix histopathology","Rat",24,"Months","Inhalation",700,"ppm","Increase","Increase 700 (cervical squamous epithelial hyperplasia was observed in 5% (3/60) of high dose females at 24 months (compared to 0% in controls)., Absolute)","1/1 study observed effects on cervix histopathology after 24 months exposure. No systemic toxicity (bw) was observed in the females from this study."]
[5,"EATS-mediated","Estrus cyclicity","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increased cumulative number of days (6966) in estrogen-predominant days (proestrous and estrous) in the estrous cycle in D4 group compared to controls (4152). Percent also increased. ","2/2 studies observed effects on the estrous cycle. Increased cycle incidence and number of estrogen-predominant days in aging rats as well as abnormal estrous cycles (longer and irregular)  in F1 females after developmental and continued adult exposure were observed. No effects were observed in F0 rats after adult exposure. No systemic toxicity was observed in these studies (bw, clinical signs, food consumption). "]
[5,"EATS-mediated","Estrus cyclicity","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increased mean estrous cycle incidence compared to control"]
[5,"EATS-mediated","Estrus cyclicity","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increased duration of proestrous/estrous phases (2.4-3.5 days/cycle compared to control with 1-2 days/cycle)"]
[8,"EATS-mediated","Estrus cyclicity","Rat","107-125 (F0) ","Days","Inhalation",null,"ppm","No effect","No evidence of exposure-related effects in F0 rats"]
[8,"EATS-mediated","Estrus cyclicity","Rat"," ≥138 days (F1)","Days","Inhalation",700,"ppm","Increase","15/30 F1 females in the 700 ppm group were anovulatory or had longer estrous cycles (5.3 days compared to 4.2 in controls)"]
[8,"EATS-mediated","Estrus cyclicity","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","Increase","The number of F1  non-pregnant rats with estrous cycle irregularities\nwas 2/4, 8/10, 5/9, 10/12, and 15/18 in control, 70, 300, 500,\nand 700 ppm groups, respectively. No statistical assessment was made. "]
[8,"EATS-mediated","Mammary gland histopathology (female)","Rat","107-125 (F0) ","Days","Inhalation",null,"ppm","No effect","No effect (No evidence of exposure-related effects, Absolute) (F0)","1/1 study found histopathological changes in mammary glands in F1 females after developmental and continued adult exposure, however, no statistical assessments were made and no effects were observed in F0 females. No systemic toxicity was observed in this study (bw, clinical signs, food consumption). "]
[8,"EATS-mediated","Mammary gland histopathology (female)","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm",null," (Number of mammary gland changes with ductal/acinar and/or lobular proliferation with secretory activity was 1, 6, 3, 5, 11 and number of rats with duct ectasia galactocele was 0, 3, 3, 1, 6 in control, 70, 300, 500, 700 ppm D4, respectively (out of groups of 30 animals). No statistical analysis was made. , Absolute) (F1)"]
[5,"EATS-mediated","Ovary histopathology","Rat",14,"Months","Inhalation",700,"ppm","Decrease","Decrease 700 (Decrease (37%) in the incidence of antral-size atretic follicles in the ovaries, Absolute)","4/5 studies found histopathological changes in the ovaries of D4-exposed females. Changes occurred after adult exposure (24 months and 3 months but not after 4 months in the 2 gen study or 3 days) and in aging rats as well as after developmental and continued adult exposure. "]
[4,"EATS-mediated","Ovary histopathology","Rat",24,"Months","Inhalation",700,"ppm","Increase","Increase 700 (ovarian atrophy presented in 6.7% (4/60) of high dosed females at 24 months (compared to 1.7% in controls). , Absolute)"]
[9,"EATS-mediated","Ovary histopathology","Rat",3,"Months","Inhalation",898,"ppm","Increase","Increase 898 (Ovarian hypoactivity, meaning absence of corpora lutea; normal follicular development present, was increased in incidence in\nfemale rats from the 898-ppm exposure group (9/20 compared to 1/20 in control). No statistical analysis was carried out. The effect was not observed after 1 month recovery period (10 animals/group). , Absolute)"]
[7,"EATS-mediated","Ovary histopathology","Rat",3,"Days","Inhalation",null,"ppm","No effect","No change in the number of Corpora lutea was detectable among ovulating rats"]
[8,"EATS-mediated","Ovary histopathology","Rat","107-125 (F0) ","Days","Inhalation",null,"ppm","No effect","No effect (No evidence of exposure-related effects, Absolute)"]
[8,"EATS-mediated","Ovary histopathology","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","Increase","Increase (Number of non-pregnant rats with abnormal ovaries and devoid of corpora lutea were increasing with exposure from 2/4, 6/10, 4/9, 5/12 and 13/18 in the control, 70, 300, 500, and 700ppm groups, respectively. No statistical analysis was performed. , Absolute)"]
[5,"EATS-mediated","Ovary weight","Rat",14,"Months","Inhalation",700,"ppm","No effect","No effect 700 (No effect, Absolute and relative)","3/5 studies reported decreased ovary weight after  ≥700 ppm D4 exposure. No effects were observed in a study with aging rats (5), or in a 2 generation study (8). In adult rats, short diestrus and/or proestrus exposure decreased ovary weight if exposure continued during proestrus (7) and 3 months repeated exposure also decreased ovary weight (9)  - an effect that, however, was not observed after 1 month recovery. Lastly, 6 days of exposure for 3 days before mating and until GD3 decreased ovary weight (bw gain was also decreased in these animals), whereas other exposure scenarios (28 days pre-mating to GD19, 31 days pre-mating to 3 days pre-mating, GD2-5) in the same study (6) did not affect ovary weights (despite affecting bw gain as well). "]
[9,"EATS-mediated","Ovary weight","Rat",3,"Months","Inhalation",898,"ppm","Decrease","Decrease 898 (Decreased in the 898 ppm exposure group (62% of control). But no effect was observed in animals that was allowed 1 month recovery (10 animals), Absolute and relative to brain weight)"]
[7,"EATS-mediated","Ovary weight","Rat",2.1,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[7,"EATS-mediated","Ovary weight","Rat",3,"Days","Inhalation",900,"ppm","Decrease","Decrease 900 (Decreased ovarian weight was observed in the 900 ppm group, both absolute and relative to body weight and brain weight, Absolute and relative)"]
[6,"EATS-mediated","Ovary weight","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"EATS-mediated","Ovary weight","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"EATS-mediated","Ovary weight","Rat",6,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Mean absolute maternal ovary weight was decreased in the 700 ppm group by 10.1% compared to control, Absolute)"]
[6,"EATS-mediated","Ovary weight","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[8,"EATS-mediated","Ovary weight","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect on ovary weight, Absolute and relative)"]
[7,"EATS-mediated","Oviduct histopathology","Rat",3,"Days","Inhalation",700,"ppm","Decrease","Reduction in the mean number of ova in the oviducts on the day of estrus in\nboth exposure groups (4.8±0.97 and 2.8±0.71 ova/rat) relative to controls (8.7±0.78 ova/rat)","1/1 study reported effects on oviduct histopathology. "]
[5,"EATS-mediated","Uterus histopathology (with cervix)","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increase 700 (An increased incidence of cystic endometrial hyperplasia was observed (14/37 compared to control with 8/37), Absolute)","2/4 studies reported effects on uterus histopathology. Both studies reported an increased incidence of cystic endometrial hyperplasia in adult (24 months exposure) and aging rats (14 months exposure), respectively. After 24 months adult exposure endometrial adenomas were also observed, those were not observed in the control group.  3-4 months exposure did not induce effects on uterine histopathology.   "]
[4,"EATS-mediated","Uterus histopathology (with cervix)","Rat",24,"Months","Inhalation",700,"ppm","Increase","An increased incidence of uterine cystic endometrial hyperplasia (from 19 % in controls to 50 % in treated females) was found in females exposed to 700 ppm D4. "]
[4,"EATS-mediated","Uterus histopathology (with cervix)","Rat",24,"Months","Inhalation",null,"ppm","No effect","No effect (No statistically  significant effect of D4 on incidence of uterine neoplasia, Absolute) But an increased incidence of endometrial adenoma was observed (4/60 in 700 ppm group vs 0/60 in the controls) this effect was not statistically significant. "]
[9,"EATS-mediated","Uterus histopathology (with cervix)","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[8,"EATS-mediated","Uterus histopathology (with cervix)","Rat","107-125 (F0) ","Days","Inhalation",null,"ppm","No effect","No effect (No evidence of exposure-related effects, Absolute)"]
[5,"EATS-mediated","Uterus weight (with cervix)","Rat",14,"Months","Inhalation",700,"ppm","No effect","No effect 700 (No effect, Absolute and relative)","2/3 studies reported effects on uterine weight. 24 months adult exposure increased the uterine weight whereas 14 months in aging rats did not. In contrast 3 days exposure during diestrus and proestrus decreased the relative uterine weight, whereas 2.1  days did not. In this last study, bw was also decreased. "]
[4,"EATS-mediated","Uterus weight (with cervix)","Rat",24,"Months","Inhalation",700,"ppm","Increase","Increase 700 (Uterine weight (absolute and relative) was increased (24%) in the 700 ppm exposure group at 24 months. , Absolute and relative)"]
[7,"EATS-mediated","Uterus weight (with cervix)","Rat",2.1,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[7,"EATS-mediated","Uterus weight (with cervix)","Rat",3,"Days","Inhalation",900,"ppm","Decrease","Decrease 900 (Decreased uterus/body weight in 900 ppm group compared to control, Relative)"]
[5,"EATS-mediated","Vagina histopathology","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increase in severity was observed for epithelial thickness compared to controls","2/3 studies showed effect on vagina histopathology. Aging and adult rats showed increased mucification and epithelial thickness. In adult rats this was concomitant with an increase in number of diestrus rats. In the 2 gen study this effect was not observed in F0 females after 4 months adult and gestational exposure. "]
[5,"EATS-mediated","Vagina histopathology","Rat",14,"Months","Inhalation",700,"ppm","Change","Change 700 (D4-exposed animals also had a slightly lower incidence of vaginal mucification than controls – but for those animals in the D4-group that did display mucification there was a shift to moderate and severe severity.)"]
[9,"EATS-mediated","Vagina histopathology","Rat",3,"Months","Inhalation",898,"ppm","Increase","More female rats from the\n898-ppm exposure group appeared to be in the diestrus stage of the rat estrous cycle (18/20 rats compared to 9/20 in control). No statistical analysis was made. At the end of\nthe 1-month recovery phase, the estrous cycle, as inspected by\nthe vaginal changes in the control and highest-exposure group,\nwere similar"]
[9,"EATS-mediated","Vagina histopathology","Rat",3,"Months","Inhalation",898,"ppm","Increase","Increase 898 (Muci\u008efication of the vaginal mucosa was increased\nin incidence and the thickness of the mucinous cell layer\nwas more prominent in the 898ppm-exposure group (19/20 rats compared to 9/20 in control). No statistical analysis was made. After 1 month recovery no effects were observed (10 animals/group). , Absolute)"]
[8,"EATS-mediated","Vagina histopathology","Rat","107-125 (F0) ","Days","Inhalation",null,"ppm","No effect","No effect (No evidence of exposure-related effects, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Fertility (mammals)","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No effect of D4 on fertility indices compared to control, Absolute)","2/2 studies reported effects on fertility index. The first study (6) showed that a specific exposure at 1 day before mating decreased the fertility index, whereas other exposure scenarios (28 days pre-mating to GD19, 4 days pre-mating to GD1/3 or GD0-2) did not. In the 2 gen study, fertility and number of pregnant rats decreased only in the F1 females after developmental and continued adult exposure. "]
[6,"Sensitive to, but not diagnostic of, EATS","Fertility (mammals)","Rat",1,"Day","Inhalation",700,"ppm","Decrease","Decrease 700 (Fertility index decreased after D4 exposure 1 day before mating (64.7%) compared to control (95.5%). , Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Fertility (mammals)","Rat","4-6","Days","Inhalation",null,"ppm","No effect","No effect (No effect on fertility index (%), Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Fertility (mammals)","Rat","1-3","Days","Inhalation",null,"ppm","No effect","No effect (No effect of short post-mating exposure on fertility index (%), Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Fertility (mammals)","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Fertility indices (%) were not affected in F0 rats but were decreased in 700 ppm F1 males and females (77% compared to 100% in controls), Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Fertility (mammals)","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","Increase","Increase (Number of non-pregnant F1 rats were increasing with exposure (4/30, 10/30, 9/30, 12/30, 18/30 in control, 70, 300, 500, and 700 ppm group respectively). No statistical assessment was made. , Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Gestation length","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Increase","Increase 700 (Gestation length was increased in F1 700ppm rats (22.1 days compared to 21.6 days in controls), but not in F0 rats., Absolute)","1/1 study showed an increased gestational length in F1 rats after developmental and continued adult and gestational exposure."]
[8,"Sensitive to, but not diagnostic of, EATS","Litter size","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",500,"ppm","Decrease","Decrease 500 (Reductions in total litter sizes and live pups/litter were observed in the 500 and 700 ppm\ngroups in the F0 generation and for the F1 animals in the first mating. No effects were observed on litter size when the F1 males were paired with unexposed females., Relative (per litter))","1/1 study showed  a reduced litter size in F0 and F1 females. Bw gains (but not general bws) were also decreased in this study in accordance with fewer  fetuses. "]
[6,"Sensitive to, but not diagnostic of, EATS","Litter viability","Rat",37,"Days","Inhalation",500,"ppm","Decrease","Decrease 500 (Number of viable fetuses was decreased in 500 and 700 ppm groups, Absolute)","2/2 studies showed effects on litter viability. Number of viable litters decreased following exposure from 28 days pre-mating to GD19 and 3 days pre-mating to GD3, but not 31 days pre-mating to 3 days pre-mating or GD2-5. In a 2 gen study 5 litter losses were observed in the 500 ppm F0 females. Bw gains (but not general bws) were also decreased in these studies in accordance with fewer viable fetuses. "]
[6,"Sensitive to, but not diagnostic of, EATS","Litter viability","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Litter viability","Rat",6,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Decreased number of viable fetuses in D4 group (61% of control)., Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Litter viability","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Litter viability","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",500,"ppm","Increase","Increase 500 (Litter loss: The number of total litter losses was comparable to controls in the F0 litters and all F1 litters (F2a, F2b, and F2c) except in the F0\n500 ppm group where 5 litter losses were observed, Relative (per litter))"]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat",37,"Days","Inhalation",300,"ppm","Decrease","Decrease 300 (Decreased number of corpora lutea in 300 (90% of control) and 500 (87% of control) ppm groups. Decreased number of implantation sites in 500 (79% of control) and 700 (68% of control) ppm groups, Absolute)","2/2 studies observed effects on number of implantations/corpora lutea.  Number of corpora lutea was decreased following exposure from 28 days pre-mating to GD19 and 3 days pre-mating to GD3, but not 31 days pre-mating to 3 days pre-mating, GD0-2, day 4/3/2/1 pre-mating, or GD2-5. In a 2 gen study F0 females had lower number of implantation sites whereas F1 females had fewer corpora lutea. "]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat",6,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Number of corpora lutea decreased in D4 group (85% of control). Number of implantation sites decreased (69% of control), Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat",1,"Day","Inhalation",null,"ppm","No effect","No effect (No effect of exposure on corpora lutea or number of implantation sites, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat","4-6","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Decreased number of corpora lutea in 'day -3 to GD3' exposure group (87% of control). No statistically significant effect on number of implantation sites. , Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat","1-3","Days","Inhalation",null,"ppm","No effect","No effect (No effect of short post-mating exposure on number of corpora lutea or number of implantation sites , Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat"," ≥138 days (F1)","Days","Inhalation",null,"ppm","Decrease","Decrease (Number of rats with corpora lutea of pregnancy\nwas 26/30, 20/30, 21/30, 18/30, and 12/30 rats in the control,\n70, 300, 500, and 700 ppm groups, respectively. No statistical analysis was made., Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm",null," (Number of non-pregnant rats with reduced numbers or only old corpora lutea was present in all exposure groups but not in control (0/4, 2/10, 1/9, 5/12, 2/18 for control, 70, 300, 500, 700 ppm, respectively). No statistical analysis was made. , Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Number of implantations, corpora lutea","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Number of implantation sites was lower in 700 ppm F0 females (73% of control), whereas this parameter was not affected in F1 females. , Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Number of ovarian follicles","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No treatment-related differences in ovarian primordial follicle counts or number of sections with growing follicles present. , Absolute)","0/1 studies found effects on follicle counts. "]
[6,"Sensitive to, but not diagnostic of, EATS","Post implantation loss","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No statistically significant effect on % post-implantation loss in D4 groups, but absolute number increased with exposure from 500 ppm D4 (control 7.8%, 30 ppm D4 6.1%, 300ppm D4 7.5, 500 ppm D4 11.3%, 700 ppm D4 16.6%), Absolute)","1/1 study found increased post-implantation loss if exposure was from 3 days pre-mating to GD3 but not pre-mating exposure only, GD2-5 only, or from 28 days pre-mating to GD19. "]
[6,"Sensitive to, but not diagnostic of, EATS","Post implantation loss","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Post implantation loss","Rat",6,"Days","Inhalation",700,"ppm","Increase","Increase 700 (Increased post-implantation loss in D4 group (18%) compared to control (6.4%). , Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Post implantation loss","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat",37,"Days","Inhalation",700,"ppm","Increase","Increase 700 (Increased % pre-implantation loss in 700 ppm group, Absolute)","1/1 study found increased pre-implantation loss if exposure was from 3 days pre-mating to GD3 or from 28 days pre-mating to GD19, but not pre-mating exposure only, GD2-5, GD0-2, or 3 days pre-mating to GD1/3"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat",6,"Days","Inhalation",700,"ppm","Increase","Increase 700 (Increased in D4 group (28.4%) compared to control (9.8%)., Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat",1,"Day","Inhalation",null,"ppm","No effect","No effect (No effect on % pre-implantation loss, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat","4-6","Days","Inhalation",null,"ppm","No effect","No effect (No effect on % pre-implantation loss, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Pre implantation loss","Rat","1-3","Days","Inhalation",null,"ppm","No effect","No effect (No effect of short post-mating exposure on % pre-implantation loss , Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Pup survival index","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Pup survival of F2b pups was significantly reduced\n(p < 0.05) in the 700 ppm offspring at PND 0 (87.6% compared to 97.8% in control). No other relevant\neffects on pup survival were noted, Relative (per litter))","1/1 study found reduced pup survival in the F2 generation. "]
[6,"Sensitive to, but not diagnostic of, EATS","Time to mating","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","0/2 studies found effects on time to mating."]
[6,"Sensitive to, but not diagnostic of, EATS","Time to mating","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Time to mating","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"[Not in list]","[Not in list]","Rat",37,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Gravid uterine weight decreased after 700 ppm D4 exposure, Absolute)","1/1 study showed decreased gravid uterine weights following exposure from  3 days pre-mating to GD3 or from 28 days pre-mating to GD19, but not pre-mating exposure only, or GD2-5, or GD0-2."]
[6,"[Not in list]","[Not in list]","Rat",6,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Gravid uterine weight decreased after 700 ppm D4 exposure, Absolute)"]
[6,"[Not in list]","[Not in list]","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect on gravid uterine weight, Absolute)"]
[6,"[Not in list]","[Not in list]","Rat",1,"Day","Inhalation",null,"ppm","No effect","No effect (No effect on gravid uterine weight, Absolute)"]
[6,"[Not in list]","[Not in list]","Rat","4-6","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Decreased gravid uterine weight in 'day -3 to GD3' exposure group, Absolute)"]
[6,"[Not in list]","[Not in list]","Rat","1-3","Days","Inhalation",null,"ppm","No effect","No effect (No effect of short post-mating exposure on gravid uterine weight, Absolute)"]
[6,"[Not in list]","[Not in list]","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect on gravid uterine weight, Absolute)"]
[7,"[Not in list]","[Not in list]","Rat",3,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Exposure to D4 at 700 and 900 ppm significantly decreased the proportion of rats\nthat ovulated (79% of controls, 42% of 700 ppm, and 31% of 900 ppm exposed rats)., Absolute)","1/1 study showed decreased number of ovulating rats following short diestrus and proestrus exposure."]
[8,"[Not in list]","[Not in list]","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Mating indices (%) were not affected in F0 rats but in F1 males and females in the 700 ppm group they were decreased (down to 53-55% compared to 93% in controls). , Absolute)","1/1 study reported decreased mating indices in F1 males and females following developmental and continued adult exposure."]
[8,"[Not in list]","[Not in list]","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",500,"ppm","Decrease","Decrease 500 (Litter number: The number of litters produced in the F1 generation in the\n700 ppm group for the first mating and in the 500 and 700 ppm\ngroups for the second mating were significantly reduced (59%, 65% and 46% of control, respectively)., Relative (per litter))","1/1 study reported decreased number of litters produced in an F1 generation after developmental and continued adult exposure.  "]

{"sheet":"LoE males AOs","index":12,"n_rows":18,"n_cols":14,"rows_kept":18,"cut":false,"hidden":false,"merged":[[9,11,11,11],[12,11,14,11],[15,11,16,11],[1,12,17,12]]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[8,"EATS-mediated","Age at balanopreputial separation","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","0/1 study showed effects of developmental exposure to D4 (up 700 ppm) on age at balanopreputial separation.","Weak evidence for effects on the male reproductive system with effects on testis weight and histopathology and mating indices."]
[8,"EATS-mediated","Ano-Genital distance","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","0/1 study showed effects of developmental exposure to D4 (up 700 ppm) on male anogenital distance."]
[9,"EATS-mediated","Epididymis histopathology","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","0/1 study showed effects of adult exposure to D4 (up to 898 ppm) for 3 months on epididymis histology.  "]
[8,"EATS-mediated","Mammary gland histopathology (male)","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect observed, Absolute)","0/1 showed effects of developmental exposure to D4 (up 700 ppm) on male anogenital distance."]
[9,"EATS-mediated","Prostate histopathology (with seminal vesicles and coagulating glands)","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)","0/1 study showed effects of adult exposure to D4 (up to 898 ppm) for 3 months on prostate histology.  "]
[8,"EATS-mediated","Sperm morphology","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect in any groups of F0 or F1 males, Absolute)","0/1 study showed effects on sperm morphology following adult or developmental and continued adult exposure (F0 and F1 generations). "]
[8,"EATS-mediated","Sperm motility","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect in any groups of F0 or F1 males, Absolute)","0/1 study showed effects on sperm motility following adult or developmental and continued adult exposure (F0 and F1 generations). "]
[8,"EATS-mediated","Sperm numbers","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",70,"ppm","Change","Change 70 (Statistically significant increases in testicular sperm numbers and sperm production\nrate were seen in all F0 exposed groups. However, the concurrent\ncontrol group value for sperm numbers was unusually low\nrelative to contract laboratory historical data and the control\ngroup value for the F1 males. In addition, similar effects were\nnot observed on epididymal sperm numbers and no effects were observed in F1 males, Absolute)","1/1 study showed increased testicular sperm numbers after adult exposure to D4 (up to 700 ppm), however the control values were unusually low compared to historical data and this effect may thus not be true. In this same study an effect on this endpoint was not observed after developmental and continued adult exposure (F1 males). "]
[4,"EATS-mediated","Testis histopathology","Rat",24,"Months","Inhalation",150,"ppm","Increase","Increased incidence of interstitial cell hyperplasia at 24 months of 21.7% (13/60) after exposure to 150 ppm D4, and 26.7% (16/60) after exposure to 700 ppm D4. Controls showed an incidence of 11.7%. ","1/2 studies showed effects on testis histopathology with increased incidence of interstitial cell hyperplasia after 24 months adult exposure (up to 700 ppm), this effect was not observed after 3 months adult exposure (up to 898 ppm). "]
[4,"EATS-mediated","Testis histopathology","Rat",24,"Months","Inhalation",null,"ppm","No effect","No effect (No effect of D4 on testis interstitial cell adenoma, Absolute)"]
[9,"EATS-mediated","Testis histopathology","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[4,"EATS-mediated","Testis weight","Rat",24,"Months","Inhalation",700,"ppm","Increase","Increase 700 (Testes weight increase was observed at 12- (8.6% absolute, 8.5% relative to body weight)  and 24-month (21% absolute, 28% relative to body weight) exposure periods for males exposed to 700 ppm D4. After a 12 month recovery period increased absolute (67%), relative to body (67.5%) and brain (66.5%) weight, testis weights were still observed in the 700ppm group. , Absolute and Relative)","2/3 studies showed increased testis weight following 24 months adult exposure (relative) and 3 months adult exposure (absolute). In the 24 months study, a concomitant small decrease in body weight (around 6%) was observed at necropsy. No effects on body weight were observed in the 3 months study but the effects on testis weight were only observed in the 488 ppm group and not the high dose of 898 ppm D4. In the third study neither adult exposure or developmental and continued adult exposure up to 700 ppm D4 affected testis weights. "]
[8,"EATS-mediated","Testis weight","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",null,"ppm","No effect","No effect (No effect on left or right testis weight, Absolute and relative)"]
[9,"EATS-mediated","Testis weight","Rat",3,"Months","Inhalation",488,"ppm","Increase","Increase 488 (Increased testis weight (117% of control) after 3 months exposure to 488 ppm - no effect was observed at 898 ppm., Absolute)"]
[8,"[Not in list]","[Not in list]","Rat","107-125","Days","Inhalation",null,"ppm","Change","Change (Ejaculatory plug production increased with exposure and was 0.033, 0.023, 0.058, 0.332 and 0.600 plugs/rat/day in the 0, 70, 300, 500 and 700 ppm groups,\nrespectively. No statistical analysis was performed., Absolute)","1/1 study showed increased ejaculatory plug production after both adult (F0 males) and developmental and continued adult exposure (F1 males). "]
[8,"[Not in list]","[Not in list]","Rat","≥138 days","Days","Inhalation",null,"ppm","Change","Change (Ejaculatory plug production increased with exposure and was 0.027, 0.030, 0.052, 0.112 and 0.425 plugs/rat/day in the 0, 70, 300, 500 and 700 ppm groups,\nrespectively. No statistical analysis was performed., Absolute)"]
[8,"[Not in list]","[Not in list]","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Mating indices (%) were not affected in F0 rats but in F1 males and females in the 700 ppm group they were decreased (down to 53-55% compared to 93% in controls). , Absolute)","1/1 study showed decreased mating indices following developmental and continued adult exposure to 700 ppm D4 (F1 males), this effect was not observed after adult exposure only (F0 males). "]

{"sheet":"LoE in vitro mechanistic","index":13,"n_rows":9,"n_cols":14,"rows_kept":9,"cut":false,"hidden":false,"merged":[[2,11,4,11],[5,11,7,11],[1,12,8,12]]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[13,"In vitro mechanistic","Cellular proliferation","Human",21,"Days","Uptake from the medium (in vitro)",0.01,"µM","Increase","Increase 0,01 (D4 increased cell proliferation statistically significant from 0.01 µM. The increases were larger than the positive control (70 nM 17β-oestradiol) from around 1 µM D4. , Absolute)","1/1 study showed increased cell proliferation following exposure to D4 in a similar manner to effects induced by 17β-estradiol. ","Evidence for estrogenic mode of action including Erα binding and activation as well as affecting estrogen-dependent gene and protein expression."]
[2,"In vitro mechanistic","Estrogen receptor","Human",4,"Hours","[Not in list]",900,"ppm","Increase","Increase 900 (D4 bound Erα, inhibiting estradiol binding with 20%, Absolute)","2/2 studies found effects of D4 on Erα indicating both Erα binding and activation of D4. "]
[2,"In vitro mechanistic","Estrogen receptor","Human","?","?","Uptake from the medium (in vitro)",10,"µM","Increase","Increase 10 (D4 increased ERα reporter gene activation by 5-fold in MCF-7 cells, Relative)"]
[3,"In vitro mechanistic","Estrogen receptor","Human",30,"Minutes","[Not in list]","4.0 × 10−5 ","Molar","Increase","Increase 4.0 × 10−5  (D4 decreased E2 binding to ERα (approximately by 25%) but not Erβ indicating a competitive binding of D4 to Erα. , Absolute)"]
[2,"In vitro mechanistic","Progesterone (in vitro)","Human",4,"Hours","[Not in list]",null,"ppm","No effect","No effect (D4 did not affect PRα and β, Absolute)","0/1 study showed effects of D4 on the progesterone receptor. "]
[2,"In vitro mechanistic","Progesterone (in vitro)","Human","?","?","Uptake from the medium (in vitro)",null,"µM","No effect","No effect (D4 did not affect PRα and β reporter gene activity, Relative)"]
[2,"In vitro mechanistic","Progesterone (in vitro)","Human","?","?","Uptake from the medium (in vitro)",null,"Molar","No effect","No effect (D4 did not affect PRα in HitHunter assay, Relative)"]
[1,"[Not in list]","[Not in list]","Rat",1,"Days","Uptake from the medium (in vitro)","1.0 × 10−5 ","Molar","Change","Change 1.0 × 10−5  (Increased CaBP-9K (10-fold gene expression compared to control), decreased Erα (0.6-fold gene expression) and increased PR (1.5-fold gene expression) gene and protein expression. , Expression levels relative to stable reference genes or proteins)","1/1 study showed increased expression (both transcript and protein level) of estrogen-dependent gene, CaBP-9K, and the progesterone receptor, but decreased expression of Erα. "]

{"sheet":"LoE in vivo mechanistic","index":14,"n_rows":31,"n_cols":14,"rows_kept":31,"cut":false,"hidden":false,"merged":[[1,11,5,11],[6,11,8,11],[13,11,15,11],[18,11,19,11],[20,11,27,11],[16,11,17,11]]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[3,"In vivo mechanistic","Estradiol level","Mouse",7,"Days","Oral",10,"mg/kg bw/day","Decrease","Decrease 10 (Serum estradiol was reduced by approximately 50 % by D4 exposure of 1000 mg/kg bw/day. Estradiol levels decreased in a dose-dependent manner from 10 mg/kg bw/day. This was however not statistically assessed. , Absolute & relative)","3/3 studies found effects on serum estrogen concentrations. The effects were however opposing with decreased serum estrogen following 7 days oral exposure and 14 moths inhalation exposure and increased serum estrogen after a short 2-3 day inhalation exposure specifically during diestrus and proestrous. In the 7 day exposure scenario, the hypothesis of increased corticosterone levels leading to decreased estrogen levels was rejected by the observation of a decrease in estrogen levels in exposed adrenalectomized mice.  "]
[3,"In vivo mechanistic","Estradiol level","Mouse",7,"Days","Oral",1000,"mg/kg bw/day","Decrease","Decrease 1000 (Serum estradiol was reduced in intact, sham-operated and adrenalectomized mice, Absolute)"]
[5,"In vivo mechanistic","Estradiol level","Rat",14,"Months","Inhalation",700,"ppm","Decrease","Decrease 700 (Decreased serum estradiol over the entire study period (maximally around 167% increased compared to control, assessed from graph), Absolute per liter serum)"]
[7,"In vivo mechanistic","Estradiol level","Rat",2.1,"Days","Inhalation",700,"ppm","Increase","Increase 700 (Increases in plasma estrone levels but not estradiol or estrone/estradiol ratios were observed at 700 and 900 ppm, Absolute)"]
[7,"In vivo mechanistic","Estradiol level","Rat",3,"Days","Inhalation",700,"ppm","Increase","Increase 700 (Mean plasma E2 levels on the morning of estrous were elevated\nin the 700 and 900 ppm exposure groups (22.2±4.3 and\n21.2±1.8 pg/mL, respectively) compared to the control group\n(7.76±1.4 pg/mL). Plasma E1 levels in D4-treated rats were significantly\nhigher in both the 700 (72.0±3.4 pg/mL) and 900 ppm\n(79.1±4.4 pg/mL) exposure groups relative to controls\n(51.5±3.1 pg/mL). Statistically significant\nreductions in E1/E2 ratios were observed both in the 700\nand 900 ppm exposure groups relative to the plasma E1/E2\nratios in control rats., Absolute)"]
[5,"In vivo mechanistic","Follicle Stimulating Hormone (FSH) level","Rat",14,"Months","Inhalation",700,"ppm","No effect","No effect 700 (12% lower serum FSH levels at necropsy but no statistical significance, Absolute per liter serum)","1/2 studies found decreased FSH levels. The effect was observed after 3 days exposure during estrus and proestrous but not after 2.1 day exposure during diestrus. A non-statistically significant decrease of 12% was also observed in another study following 14 months exposure of aging rats. "]
[7,"In vivo mechanistic","Follicle Stimulating Hormone (FSH) level","Rat",2.1,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[7,"In vivo mechanistic","Follicle Stimulating Hormone (FSH) level","Rat",3,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Mean plasma FSH levels on the morning of estrous were decreased after both 700 and 900 ppm D4 exposure, Absolute)"]
[2,"In vivo mechanistic","LABC weight (Hershberger)","Rat",10,"Days","Inhalation",null,"ppm","No effect","No effect (D4 did not affect ventral prostate (fixed or fresh), seminal vesicles, LABC muscle, glans penis, or Cowper's gland weights, nor affect TP-induced weight increase., Absolute)","0/1 study showed effects in the Hershberger assay. "]
[7,"In vivo mechanistic","Luteinizing Hormone (LH) level","Rat",3,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Plasma LH levels were lower than controls at the 4, 6, and 8 p.m. time points\nin the 700 ppm exposure group, achieving a significant reduction\nonly at the 6 p.m. time point (7.9±1.7 ng/mL compared with\n14.2±2.2 ng/mL in the controls). Significantly lower\nLH levels were observed at the 4, 6, and 8 p.m. measurements\nin the 900 ppm exposure group. The area under the LH\ncurve was also significantly less in the 900 ppm group, but not\nin the 700 ppm group, relative to controls. When grouped by ovulatory status, ovulating or non-ovulating rats, there were no treatment-related differences in the mean plasma LH levels. Every animal that failed to produce an LH surge failed to ovulate., Absolute)","1/1 study showed decreased LH levels following a short 3 day exposure during diestrus and proestrous.  "]
[3,"In vivo mechanistic","Other hormones","Mouse",7,"Days","Oral",1000,"mg/kg bw/day","Increase","Increase 1000 (Serum corticosterone increased in D4-exposed intact and sham-operated mice but not in adrenalectomized mice., Absolute)","1/1 study found increased corticosterone levels following 7 days exposure. "]
[1,"In vivo mechanistic","Phase I enzyme induction (in vivo)","Rat",4,"Days","Direct",500,"mg/kg bw/day","Increase","Increase 500 (Increased CYP2B1 gene expression in liver (10-fold (500 mg), 30-fold (1000mg) compared to control), Relative to 18S expression)","1/1 study found increased CYP2B1 gene expression in liver from D4 exposed rats. Possibly a D4 metabolizing enzyme. "]
[5,"In vivo mechanistic","Progesterone","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increase 700 (Increased serum progesterone from week 2-10 out of 57 weeks (approximately 40% increased compared to control, assessed from graph), Absolute per liter serum)","2/2 studies found increased progesterone levels observed in aging rats after 2-10 weeks exposure and in adult rats after 2.1 days exposure during proestrous and beginning of diestrus (but not after 3 days exposure during pro- and diestrus). "]
[7,"In vivo mechanistic","Progesterone","Rat",2.1,"Days","Inhalation",900,"ppm","Increase","Increase 900 (Increased plasma progesterone levels in 900 ppm group, Absolute)"]
[7,"In vivo mechanistic","Progesterone","Rat",3,"Days","Inhalation",null,"ppm","No effect","No effect (No effects on progesterone levels on the morning of estrous, Absolute)"]
[7,"In vivo mechanistic","Prolactin","Rat",3,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Reduction in PRL levels was noted only at the\n2 p.m. time point in both exposure groups (time points: 2, 4, 6, 8, 10 p.m.), Absolute)","1/2 studies found decreased prolactin levels after 3 days exposure during diestrus and proestrous. No effects were observed in ageing rats with 14 months exposure. "]
[null,"In vivo mechanistic","Prolactin","Rat",14,"Months","Inhalation",null,"ppm","No effect","No effect on prolactin levels"]
[2,"In vivo mechanistic","Uterus histopathology (UT assay)","Rat",3,"Days","Inhalation",700,"ppm","Increase","Increase 700 (D4 exposure resulted in an increase in both the luminal (maximal increase: 2.6-fold compared to control) and glandular epithelial cell height (maximal increase: 1.6-fold compared to control) in both Sprague dawley and Fischer-344 rats., Absolute)","2/2 studies showed histopathological changes in the uteri of rats in the uterotrophic assay, where increased uterine epithelial cell height was observed."]
[10,"In vivo mechanistic","Uterus histopathology (UT assay)","Rat",4,"Days","Oral",250,"mg/kg bw/day","Increase","Increase 250 (Uterine epithelium cell height, in both strains of rats, was\nincreased in a dose-related manner following treatment with D4 at 250, 500, and 1000 mg/kg/day, Absolute)"]
[1,"In vivo mechanistic","Uterus weight (UT assay)","Rat",4,"Days","Direct",null,"mg/kg bw/day","No effect","No effect (No effect after D4 exposure , Relative to bw)","No effect was observed in Erα knockout mice, indicating an Erα-mediated effect."]
[2,"In vivo mechanistic","Uterus weight (UT assay)","Rat",3,"Days","Inhalation",700,"ppm","Increase","D4 increased wet (maximal effect: 2.7-fold in Sprague Dawley rats) and blotted (2.6-fold) uterine weight "]
[2,"In vivo mechanistic","Uterus weight (UT assay)","Rat",3,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (D4 mildly (80% of EE control) suppressed the EE-induced increase in uterine weight in Fischer 344 rats, but not in sprague dawley rats., Absolute)"]
[3,"In vivo mechanistic","Uterus weight (UT assay)","Mouse",3,"Days","Oral",250,"mg/kg bw/day","Increase","Increase 250 (Uterine weight was increased by D4 exposure in a dose-dependent manner from 250 mg/kg (approximately 140%, 150%, and 450% of control at respectively 250, 500, and 1000 mg/kg D4 assessed from graph). Pre-treatment with the ER antagonist ICI 182,780 blocked this effect (assessed at 1000 mg/kg)., Absolute)"]
[3,"In vivo mechanistic","Uterus weight (UT assay)","Mouse",3,"Days","Oral",null,"mg/kg bw/day","No effect","No effect (D4 did not induce an increase in uterus weight in Erα KO mice.  , Absolute)"]
[10,"In vivo mechanistic","Uterus weight (UT assay)","Rat",4,"Days","Oral",500,"mg/kg bw/day","Change","When 500 mg D4 was co-administered with increasing levels of Ethinyl estradiol (EE), EE-dependent\nuterine growth was decreased by half in Sprague-dawley pups\nand by nearly an order of magnitude in Fischer-344 pups. These data indicate weak antiestrogenic properties of D4."]
[10,"In vivo mechanistic","Uterus weight (UT assay)","Rat",4,"Days","Oral",250,"mg/kg bw/day","Increase","Increase 250 (Uterine weight was increased in both rat strains from 250 mg/kg D4 exposure (approximately 30% at 250 mg up to 130% at 1000 mg - increases are approximated from graphs). , Absolute & relative to bw)"]
[11,"In vivo mechanistic","Uterus weight (UT assay)","Rat",3,"Days","Oral","?","mg/kg bw/day","Increase","Increase ? (A statistically non-significant increase <20% was observed following exposure to an unknown dose of D4. , Relative to bw)"]
[1,"[Not in list]","[Not in list]","Rat",4,"Days","Direct",500,"mg/kg bw/day","Change","Increased (in the uterus) CaBP-9K gene expression (from 500 mg: 1.5-fold, 1000mg: 2.5-fold), no observable effect on protein expression (for all proteins included: assessed from Western blot, not quantified), decreased PR gene expression (1000 mg: 0.6-fold), increased PR protein expression (from 500mg), and decreased Erα gene expression (from 500 mg: 0.5-fold) and had no observable effect on ERα protein expression.","1/1 study showed increased uterine estrogen-dependent gene expression and decreased Erα gene expression, whereas progesterone receptor expression was decreased at gene expression level and increased at protein expression level. "]
[3,"[Not in list]","[Not in list]","Mouse",3,"Days","Oral",1000,"mg/kg bw/day","Increase","Increase 1000 (Uterine peroxidase activity was increased by D4 exposure (approximately 5-fold compared to control assessed from graph), Relative)","1/1 study showed increased uterine peroxidase activity."]
[5,"[Not in list]","[Not in list]","Rat",14,"Months","Inhalation",700,"ppm","Decrease","Decrease 700 (Decreased (10-30%) corticosterone levels were observed from weeks 2-51 out of 57 weeks. , Absolute per liter serum)","1/1 study showed decreased corticosterone concentrations after 2-51 weeks of exposure in aging rats. "]

{"sheet":"LoE other endocrine organs","index":15,"n_rows":26,"n_cols":14,"rows_kept":26,"cut":false,"hidden":false,"merged":[]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[4,"EATS-mediated","Thyroid histopathology","Rat",24,"Months","Inhalation",null,"ppm","No effect","No effect (No statistically significant effects on the incidence of thyroid gland c-cell neoplasia., Absolute)"]
[9,"EATS-mediated","Thyroid histopathology","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[12,"EATS-mediated","Thyroid histopathology","Rat",4,"Weeks","Inhalation",700,"ppm","Increase","Increase 700 (Cell proliferation (BrdU incorporation) was increased after 6 (8%) and 13 (7%) days. On day 27, thyroid cell proliferation in D4-treated animals had returned to control values. In a concentration-response experiment with only 6 days of exposure, no effect of D4 was observed on thyroid BrdU incorporation., Absolute)"]
[6,"EATS-mediated","Thyroid weight","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"EATS-mediated","Thyroid weight","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"EATS-mediated","Thyroid weight","Rat",6,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"EATS-mediated","Thyroid weight","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[12,"EATS-mediated","Thyroid weight","Rat",4,"Weeks","Inhalation",700,"ppm","Increase","Increase 700 (Exposure to 700 ppm D4 produced a small but statistically significant increase in thyroid weight on day 6 (17%), 13 (18%) and 27 (23%)., Relative to bw)"]
[9,"Sensitive to, but not diagnostic of, EATS","Adrenals histopathology","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[5,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",14,"Months","Inhalation",700,"ppm","No effect","No effect 700 (No effect, Absolute and relative)"]
[6,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",37,"Days","Inhalation",700,"ppm","Increase","Increase 700 (Mean absolute maternal adrenal gland weight was increased in high dose group (16.8% compared to control), Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",6,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[9,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",3,"Months","Inhalation",null,"ppm","Decrease","Decreased absolute (not relative to brain weight) weight in 898 ppm group after 1 month recovery (10 animals) (93% of control)"]
[9,"Sensitive to, but not diagnostic of, EATS","Adrenals weight","Rat",3,"Months","Inhalation",488,"ppm","Increase","Increase 488 (Increased in 488 (117% of control) and 898 (129% of control) groups. , Absolute and relative)"]
[9,"Sensitive to, but not diagnostic of, EATS","Brain histopathology examination","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[6,"Sensitive to, but not diagnostic of, EATS","Brain weight","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"Sensitive to, but not diagnostic of, EATS","Brain weight","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"Sensitive to, but not diagnostic of, EATS","Brain weight","Rat",6,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[6,"Sensitive to, but not diagnostic of, EATS","Brain weight","Rat",4,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[7,"Sensitive to, but not diagnostic of, EATS","Brain weight","Rat",2.1,"Days","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute and relative)"]
[8,"Sensitive to, but not diagnostic of, EATS","Pituitary histopathology","Rat","107-125 (F0) ","Days","Inhalation",null,"ppm","No effect","No effect (No evidence of exposure-related effects, Absolute)"]
[9,"Sensitive to, but not diagnostic of, EATS","Pituitary histopathology","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, Absolute)"]
[8,"Sensitive to, but not diagnostic of, EATS","Pituitary weight","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Increase","Increase 700 (Increased relative pituitary weight in F0 700 ppm males (OBS! the table in the paper reports the same values for control and exposed). Absolute and relative pituitary weight in F1 700 ppm females was increased (33-40%). , Absolute and relative)"]

{"sheet":"LoE target organ toxicity","index":16,"n_rows":27,"n_cols":14,"rows_kept":27,"cut":false,"hidden":false,"merged":[]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[4,"Target organ toxicity","Kidney histopathology","Rat",24,"Months","Inhalation",30,"ppm","Increase","Increase 30 (The incidence of chronic nephropathy was elevated at 24 months for females at≥ 30 ppm., Absolute)"]
[8,"Target organ toxicity","Kidney histopathology","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Increase","Increase 700 (Increased incidence of tubular mineralization in kidneys from 700 ppm exposed F0 and F1 males (data not shown). , Absolute)"]
[4,"Target organ toxicity","Kidney weight","Rat",24,"Months","Inhalation",150,"ppm","Increase","Increase 150 (The 700 ppm exposure increased male and female kidney weight (absolute and relative) after 12 and 24 months. In the 150 ppm exposure group, female but not male rats also showed increased kidney weights at 24 months. , Absolute and relative)"]
[5,"Target organ toxicity","Kidney weight","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increase 700 (Absolute (10%) and relative to bw (8%) increase in kidney weight)"]
[8,"Target organ toxicity","Kidney weight","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",300,"ppm","Increase","Increase 300 (Relative kidney weights were increased in F0 males from 300 ppm (8%-15%), absolute from 500 ppm (8-11%). For F1 males only relative kidney weights were increased (9-11%) from 500 ppm D4 exposure. In females only 700 ppm D4 in F1 females increased the absolute (13%) and relative (9%) kidney weight., Absolute and relative)"]
[9,"Target organ toxicity","Kidney weight","Rat",3,"Months","Inhalation",488,"ppm","Change","Increased in the 488 ppm group (males) at 3 months exposure and decreased after 1 months recovery period (10 animals) in the 898 ppm group"]
[9,"Target organ toxicity","Kidney weight","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (No effect, females Absolute and relative)"]
[4,"Target organ toxicity","Liver histopathology","Rat",24,"Months","Inhalation",700,"ppm","Increase","Increase 700 (increased incidence of centrilobular hypertrophy in males and a reduction in basophilic foci in females at 700 ppm at 12 and 24 months., Absolute)"]
[8,"Target organ toxicity","Liver histopathology","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",500,"ppm","Increase","Increased incidence of hepatocyte hypertrophy in F1 females after 500 and 700 ppm D4 and in F1 700 ppm males. "]
[8,"Target organ toxicity","Liver histopathology","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Increase","Increase 700 (The incidence of pigment in the liver was increased in 700 ppm F1 males. The\npigment was extracellular in periportal regions and morphologically\ncompatible with bile pigment. The incidence of bile duct\nhyperplasia was increased in 700 ppm F1 males, Absolute)"]
[9,"Target organ toxicity","Liver histopathology","Rat",3,"Months","Inhalation",null,"ppm","No effect","No treatment -related effects were observed"]
[12,"Target organ toxicity","Liver histopathology","Rat",4,"Weeks","Inhalation",700,"ppm","Increase","Indices of cell proliferation (BrdU and PCNA) showed a marked increase in hepatic cell\nproliferation (15-22%) that was not sustained at 27 days. The\ngreatest increase in the incorporation of BrdU occurred on day 6 of exposure in the left lateral, right lateral, and median lobes."]
[12,"Target organ toxicity","Liver histopathology","Rat",5,"Days","Inhalation",70,"ppm","Increase","Hepatic hyperplasia, measured by BrdU incorporation and PCNA relative\nabundance, increased in an exposure-dependent manner. The lowest exposure concentration of D4\nthat resulted in a statistically significant increase in BrdU incorporation was 70 ppm. For PCNA expression, the values at the low end of the exposure curve were variable and it is unclear from these data at what point dose-related increases begin."]
[12,"Target organ toxicity","Liver histopathology","Rat",4,"Weeks","Inhalation",700,"ppm","Decrease","Decrease 700 (D4 reduced the number of nuclei (e.g., cells)\nrelative to controls by 9% on day 6, 16% by day 13, and 11%\nby day 27 indicating hepatocellular hypertrophy. Examination of H &\nE-stained sections from D4-treated and control liver supported\nthe presence of hypertrophy; however, there were no other\nlesions that could be attributed to exposure., Absolute)"]
[1,"Target organ toxicity","Liver weight","Rat",4,"Days","Direct",1000,"mg/kg bw/day","Increase","Increase 1000 (Increased relative liver weight compared to control, statistically significant but slight increase around 10%., Relative to bw)"]
[4,"Target organ toxicity","Liver weight","Rat",24,"Months","Inhalation",30,"ppm","Increase","Increase 30 (Liver weight increases were evident at 6, 12, and 24-months exposure for both sexes. For males, the liver weight increases were associated with exposure to ≥ 30 ppm D4 at 6 months, ≥150 ppm at 12 months, and 700 ppm D4 at 24-months. Female liver weight increases were statistically significant at all three time points (6, 12, and 24 months) at 700 ppm and at 12 and 24 months with exposure to 150 ppm D4. , Absolute and relative)"]
[5,"Target organ toxicity","Liver weight","Rat",14,"Months","Inhalation",700,"ppm","Increase","Increase 700 (Absolute (35%) and relative to bw (33%) increase in liver weight)"]
[8,"Target organ toxicity","Liver weight","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",300,"ppm","Increase","Increase 300 (Increased relative liver weight (9-18.5%) in 300, 500, and 700 ppm males, also absolute weight in 700 ppm males (16%). In F0 females, absolute and relative liver weights were increased (9-33%) after 300, 500, and 700 ppm D4 exposure. For F1 females, absolute and relative liver weights were increased (14-33%) after 500 and 700 ppm D4. , Absolute and relative)"]
[9,"Target organ toxicity","Liver weight","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (males)"]
[9,"Target organ toxicity","Liver weight","Rat",3,"Months","Inhalation",488,"ppm","Increase","Increase 488, Females (Increased in the 488 (120% of control) and 898 (125% of control) ppm groups after 3 months exposure but not after 1 month recovery., Absolute and relative to brain weight)"]
[12,"Target organ toxicity","Liver weight","Rat",4,"Weeks","Inhalation",700,"ppm","Increase","Increase 700 (Liver-to-body weight ratios were increased by 18, 20, and 22%\nrelative to controls on days 6, 13, and 27, respectively, Relative to bw)"]
[12,"Target organ toxicity","Liver weight","Rat",5,"Days","Inhalation",70,"ppm","Increase","Increase 70 (D4 increased liver weight in a dose-dependent manner., Relative to bw)"]
[8,"Target organ toxicity","Lung histopathology","Rat","107-125 (F0) or ≥138 days (F1)","Days","Inhalation",700,"ppm","Increase","Increase 700 (Significant increases in the incidence of focal alveolar histiocytosis were noted in the\nlungs of 700 ppm F0 and F1 females and the F1 males., Absolute)"]
[4,"Target organ toxicity","Spleen histopathology","Rat",24,"Months","Inhalation",30,"ppm","Increase","Increase 30 (increased incidence of hematopoietic proliferation in\nthe spleen of 700 ppm females and 30 ppm males at 24 months, Absolute)"]
[9,"Target organ toxicity","Thymus weight","Rat",3,"Months","Inhalation",null,"ppm","No effect","No effect (males)"]
[9,"Target organ toxicity","Thymus weight","Rat",3,"Months","Inhalation",488,"ppm","Decrease","Decrease 488, Females (Decreased in 488 (79% of control) and 898 (86% of control) groups. , Absolute and relative to brain weight)"]

{"sheet":"LoE systemic toxicity","index":17,"n_rows":28,"n_cols":14,"rows_kept":28,"cut":false,"hidden":false,"merged":[]}
["Study ID Matrix","Effect classification","Effect target","Species","Duration of exposure","Duration unit","Route of administration","Lowest Effect dose","Dose unit","Effect direction","Observed effect (positive and negative)","Assessment of each line of evidence","Assessment on the integrated line of evidence","Modality"]
[4,"Systemic toxicity","Body weight","Rat",24,"Months","Inhalation",700,"ppm","Decrease","Decrease 700 (Exposure had no effect on body weight or body weight gain with the exception of 700 ppm males in the 24-month exposure group. Mean body weight for this group remained approximately 6% lower than controls for the last few months on study. Statistically significant only for week 97 and at necropsy (month 24), Absolute)"]
[5,"Systemic toxicity","Body weight","Rat",14,"Months","Inhalation",null,"ppm","No effect","No effect (No treatment related effect in body weight, Absolute)"]
[6,"Systemic toxicity","Body weight","Rat",37,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Lower mean body weight gain during gestation (86% of control), Absolute)"]
[6,"Systemic toxicity","Body weight","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No effect on maternal body weight gain during gestation, Absolute)"]
[6,"Systemic toxicity","Body weight","Rat",6,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Lower mean body weight gain during gestation (87% of control), Absolute)"]
[6,"Systemic toxicity","Body weight","Rat",1,"Day","Inhalation",null,"ppm","No effect","No effect (No effect on maternal GD0-8 body weight gain, Absolute)"]
[6,"Systemic toxicity","Body weight","Rat","4-6","Days","Inhalation",700,"ppm","Increase","Increase 700 (Increased maternal GD0-8 body weight gain (128% of control) in the 'day -3 to GD1' exposure group., Absolute)"]
[7,"Systemic toxicity","Body weight","Rat",2.1,"Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Reductions in mean terminal body weight occurred in both treatment groups, relative to controls (252±2.7 and 255±2.1 g, respectively, versus 263±2.5 g, so only 3-4%.), Absolute)"]
[7,"Systemic toxicity","Body weight","Rat",3,"Days","Inhalation",900,"ppm","Decrease","Decrease 900 (Reduction in mean terminal body weight was observed only at 900 ppm\n(260±3.0 g versus 270±2.2 g in control, so only 4%), Absolute)"]
[8,"Systemic toxicity","Body weight","Rat","≥138 days","Days","Inhalation",null,"ppm","No effect","Mean weekly body weight were comparable between groups. (F1 gen)"]
[8,"Systemic toxicity","Body weight","Rat","107-125","Days","Inhalation",null,"ppm","No effect","No effect (Mean weekly body weight were comparable between groups., Absolute) (F0 gen)"]
[8,"Systemic toxicity","Body weight","Rat","≥138 days","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Maternal body weight gain during gestation was reduced in 700 ppm females (104g compared to 126g in control group). This may be the result of the reduced number of pups., Absolute)"]
[9,"Systemic toxicity","Body weight","Rat",3,"Months","Inhalation",898,"ppm","No effect","No effect 898 (Body weights of both male and female rats in the 898-ppm group\nwere slightly less (4% to 6%) than controls over the course of\nthe study. Not statistically significant, Absolute)"]
[10,"Systemic toxicity","Body weight","Rat",4,"Days","Oral",1000,"mg/kg bw/day","Decrease","Decrease 1000 (Sprague-Dawley rats in the 1000 mg group had a statistically significant reduction in\nbody weight on day 21, but not on day 22. Fisher rats had a statistically significant reduction in\nbody weight on day 23, 24, and 25. It was not possible to determine the exact % weight reduction from graphs but no effects were larger than around 10%. , Absolute)"]
[6,"Systemic toxicity","Clinical signs","Rat",37,"Days","Inhalation",null,"ppm","No effect","No effect (No treatment related clinical signs were observed, Absolute)"]
[6,"Systemic toxicity","Clinical signs","Rat",28,"Days","Inhalation",null,"ppm","No effect","No effect (No treatment related clinical signs were observed, Absolute)"]
[6,"Systemic toxicity","Clinical signs","Rat",6,"Days","Inhalation",null,"ppm","No effect","No effect (No exposure-related clinical signs were observed, Absolute)"]
[6,"Systemic toxicity","Clinical signs","Rat",4,"Days","Inhalation",null,"ppm","Change","Change (Observed in both control group and D4 exposed group, Absolute)"]
[8,"Systemic toxicity","Clinical signs","Rat","107-125","Days","Inhalation",null,"ppm","No effect","No effect (No exposure-related clinical signs were observed, Absolute)"]
[8,"Systemic toxicity","Clinical signs","Rat","≥138 days","Days","Inhalation",null,"ppm","No effect","No effect (No exposure-related clinical signs were observed, Absolute)"]
[8,"Systemic toxicity","Clinical signs","Rat","Indirect during gestation and lactation","Days","Inhalation",null,"ppm","No effect","No effect (No exposure-related clinical signs were observed, Absolute)"]
[9,"Systemic toxicity","Clinical signs","Rat",3,"Months","Inhalation",898,"ppm","Increase","Increase 898 (Clinical signs observed in one third of the females in the 898-ppm\ngroup. These clinical signs, consisting of hunched posture and\na slightly stiff gait, were of minor severity and were recorded\nonly occasionally during the \u008e rst 8 days of exposure., Absolute)"]
[10,"Systemic toxicity","Clinical signs","Rat",4,"Days","Oral",null,"mg/kg bw/day","No effect","No effect (No treatment-related clinical abnormalities observed in any of the treatment groups, Absolute)"]
[8,"Systemic toxicity","Food consumption","Rat","107-125","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Food consumption and mean body weight gain was reduced in week 1 of exposure in 700 ppm males, Absolute)"]
[8,"Systemic toxicity","Food consumption","Rat","≥138 days","Days","Inhalation",700,"ppm","Decrease","Decrease 700 (Food consumption and mean body weight gain was reduced in week 1 of exposure in 700 ppm males, Absolute)"]
[9,"Systemic toxicity","Food consumption","Rat",3,"Months","Inhalation",898,"ppm","No effect","No effect 898 (First 3 days of exposure food consumption was decreased in male (20%) and female (28%) in the 898 ppm groups. But food consumption was generally not affected over the remainder of the study. No statistically significant effects., Absolute)"]
[9,"Systemic toxicity","Mortality","Rat",3,"Months","Inhalation",898,"ppm","Increase","Increase 898 (Five females in the highest-exposure group died on days 2\n(two animals), 3, 43, and 78. Gross necropsy was unrevealing\nand the cause of death could not be determined., Absolute)"]